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    Fecal Transplantation from db/db Mice Treated with Sodium Butyrate Attenuates Ischemic Stroke Injury. Wang Huidi,Song Wei,Wu Qiheng,Gao Xuxuan,Li Jie,Tan Chuhong,Zhou Hongwei,Zhu Jiajia,He Yan,Yin Jia Microbiology spectrum The complication of type 2 diabetes (T2D) exacerbates brain infarction in acute ischemic stroke (AIS). Because butyrate-producing bacteria are decreased in T2D and butyrate has been reported to be associated with attenuated brain injury in AIS, we hypothesize that administering butyrate could ameliorate T2D-associated exacerbation of brain infarction in AIS. Therefore, we first validated that Chinese AIS patients with T2D comorbidity have significantly lower levels of fecal butyrate-producing bacteria and butyrate than AIS patients without T2D. Then, we performed a 4-week intervention in T2D mice receiving either sodium butyrate (SB) or sodium chloride (NaCl) and found that SB improved the diabetic phenotype, altered the gut microbiota, and ameliorated brain injury after stroke. Fecal samples were collected from T2D mice after SB or NaCl treatment and were transplanted into antibiotic-treated C57BL/6 mice. After 2 weeks of transplantation, the gut microbiota profile and butyrate level of recipient mice were tested, and then the recipient mice were subjected to ischemic stroke. Stroke mice that received gut microbiota from SB-treated mice had a smaller cerebral infarct volume than mice that received gut microbiota from NaCl-treated mice. This protection was also associated with improvements in gut barrier function, reduced serum levels of lipopolysaccharide (LPS), LPS binding protein (LBP), and proinflammatory cytokines, and improvements in the blood-brain barrier. Ischemic stroke is a major global health burden, and T2D is a well-known comorbidity that aggravates brain injury after ischemic stroke. However, the underlying mechanism by which T2D exacerbates stroke injury has not been completely elucidated. A large amount of evidence suggests that the gut microbiota composition affects stroke outcomes. Our results showed that the gut microbiota of T2D aggravated brain injury after ischemic stroke and could be modified by SB to afford neuroprotection against stroke injury. These findings suggest that supplementation with SB is a potential therapeutic strategy for T2D patients with ischemic stroke. 10.1128/Spectrum.00042-21
    Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity. Jais Alexander,Solas Maite,Backes Heiko,Chaurasia Bhagirath,Kleinridders André,Theurich Sebastian,Mauer Jan,Steculorum Sophie M,Hampel Brigitte,Goldau Julia,Alber Jens,Förster Carola Y,Eming Sabine A,Schwaninger Markus,Ferrara Napoleone,Karsenty Gerard,Brüning Jens C Cell High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGF(Δmyel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associated macrophage activation a homeostatic role to restore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity. 10.1016/j.cell.2016.03.033
    Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability. García-Cáceres Cristina,Quarta Carmelo,Varela Luis,Gao Yuanqing,Gruber Tim,Legutko Beata,Jastroch Martin,Johansson Pia,Ninkovic Jovica,Yi Chun-Xia,Le Thuc Ophelia,Szigeti-Buck Klara,Cai Weikang,Meyer Carola W,Pfluger Paul T,Fernandez Ana M,Luquet Serge,Woods Stephen C,Torres-Alemán Ignacio,Kahn C Ronald,Götz Magdalena,Horvath Tamas L,Tschöp Matthias H Cell We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB. 10.1016/j.cell.2016.07.028
    Diabetes and the blood-brain barrier. Kumagai Arno K The Lancet. Neurology 10.1016/s1474-4422(03)00344-2
    Effects of diabetes on brain metabolism--is brain glycogen a significant player? Sickmann Helle M,Waagepetersen Helle S Metabolic brain disease Brain glycogen, being an intracellular glucose reservoir, contributes to maintain energy and neurotransmitter homeostasis under physiological as well as pathological conditions. Under conditions with a disturbance in systemic glucose metabolism such as in diabetes, the supply of glucose to the brain may be affected and have important impacts on brain metabolism and neurotransmission. This also implies that brain glycogen may serve an essential role in the diabetic state to sustain appropriate brain function. There are two main types of diabetes; type 1 and type 2 diabetes and both types may be associated with brain impairments e.g. cognitive decline and dementia. It is however, not clear how these impairments on brain function are linked to alterations in brain energy and neurotransmitter metabolism. In this review, we will illuminate how rodent diabetes models have contributed to a better understanding of how brain energy and neurotransmitter metabolism is affected in diabetes. There will be a particular focus on the role of brain glycogen to support glycolytic and TCA cycle activity as well as glutamate-glutamine cycle in type 1 and type 2 diabetes. 10.1007/s11011-014-9546-z
    Revisiting How the Brain Senses Glucose-And Why. Bentsen Marie Aare,Mirzadeh Zaman,Schwartz Michael W Cell metabolism Glucose-sensitive neurons have long been implicated in glucose homeostasis, but how glucose-sensing information is used by the brain in this process remains uncertain. Here, we propose a model in which (1) information relevant to the circulating glucose level is essential to the proper function of this regulatory system, (2) this input is provided by neurons located outside the blood-brain barrier (BBB) (since neurons situated behind the BBB are exposed to glucose in brain interstitial fluid, rather than that in the circulation), and (3) while the efferent limb of this system is comprised of neurons situated behind the BBB, many of these neurons are also glucose sensitive. Precedent for such an organizational scheme is found in the thermoregulatory system, which we draw upon in this framework for understanding the role played by brain glucose sensing in glucose homeostasis. 10.1016/j.cmet.2018.11.001
    Advanced glycation end-products disrupt brain microvascular endothelial cell barrier: The role of mitochondria and oxidative stress. Dobi Anthony,Rosanaly Sarah,Devin Anne,Baret Pascal,Meilhac Olivier,Harry G Jean,d'Hellencourt Christian Lefebvre,Rondeau Philippe Microvascular research During diabetes mellitus, advanced glycation end-products (AGEs) are major contributors to the development of alterations in cerebral capillaries, leading to the disruption of the blood-brain barrier (BBB). Consequently, this is often associated with an amplified oxidative stress response in microvascular endothelial cells. As a model to mimic brain microvasculature, the bEnd.3 endothelial cell line was used to investigate cell barrier function. Cells were exposed to native bovine serum albumin (BSA) or modified BSA (BSA-AGEs). In the presence or absence of the antioxidant compound, N-acetyl-cysteine, cell permeability was assessed by FITC-dextran exclusion, intracellular free radical formation was monitored with HDCF-DA probe, and mitochondrial respiratory and redox parameters were analyzed. We report that, in the absence of alterations in cell viability, BSA-AGEs contribute to an increase in endothelial cell barrier permeability and a marked and prolonged oxidative stress response. Decreased mitochondrial oxygen consumption was associated with these alterations and may contribute to reactive oxygen species production. These results suggest the need for further research to explore therapeutic interventions to restore mitochondrial functionality in microvascular endothelial cells to improve brain homeostasis in pathological complications associated with glycation. 10.1016/j.mvr.2020.104098
    Reduced pericyte and tight junction coverage in old diabetic rats are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction. Liu Yedan,Zhang Huawei,Wang Shaoxun,Guo Ya,Fang Xing,Zheng Baoying,Gao Wenjun,Yu Hongwei,Chen Zongbo,Roman Richard J,Fan Fan American journal of physiology. Heart and circulatory physiology Diabetes mellitus (DM) is one of the primary pathological factors that contributes to aging-related cognitive impairments, but the underlying mechanisms remain unclear. We recently reported that old DM rats exhibited impaired myogenic responses of the cerebral arteries and arterioles, poor cerebral blood flow autoregulation, enhanced blood-brain barrier (BBB) leakage, and cognitive impairments. These changes were associated with diminished vascular smooth muscle cell contractile capability linked to elevated reactive oxygen species (ROS) and reduced ATP production. In the present study, using a nonobese T2DN DM rat, we isolated parenchymal arterioles (PAs), cultured cerebral microvascular pericytes, and examined whether cerebrovascular pericyte in DM is damaged and whether pericyte dysfunction may play a role in the regulation of cerebral hemodynamics and BBB integrity. We found that ROS and mitochondrial superoxide production were elevated in PAs isolated from old DM rats and in high glucose (HG)-treated α-smooth muscle actin-positive pericytes. HG-treated pericytes displayed decreased contractile capability in association with diminished mitochondrial respiration and ATP production. Additionally, the expression of advanced glycation end products, transforming growth factor-β, vascular endothelial growth factor, and fibronectin were enhanced, but claudin 5 and integrin β1 was reduced in the brain of old DM rats and HG-treated pericytes. Further, endothelial tight junction and pericyte coverage on microvessels were reduced in the cortex of old DM rats. These results demonstrate our previous findings that the impaired cerebral hemodynamics and BBB leakage and cognitive impairments in the same old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction. This study demonstrates that the loss of contractile capability in pericytes in diabetes is associated with enhanced ROS and reduced ATP production. Enhanced advanced glycation end products (AGEs) in diabetes accompany with reduced pericyte and endothelial tight junction coverage in the cortical capillaries of old diabetic rats. These results suggest our previous findings that the impaired cerebral hemodynamics, BBB leakage, and cognitive impairments in old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction. 10.1152/ajpheart.00726.2020
    Shared metabolic and neuroimmune mechanisms underlying Type 2 Diabetes Mellitus and Major Depressive Disorder. Duarte-Silva Eduardo,de Melo Michel Gomes,Maes Michael,Filho Adriano José Maia Chaves,Macedo Danielle,Peixoto Christina Alves Progress in neuro-psychopharmacology & biological psychiatry Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease with symptoms that go beyond the domain of glucose metabolism. In fact, research has shown that T2DM is accompanied by neurodegeneration and neuroinflammation. Interestingly, Major Depressive Disorder (MDD), a mood disorder characterized mainly by depressed mood and anhedonia is a key feature of T2DM. A body of evidence demonstrates that there are many shared neuroimmune mechanisms underlying the pathophysiology of T2DM and MDD. Therefore, here we review the state-of-art regarding the underlying factors common to both T2DM and MDD. Furthermore, we briefly discuss how depressive symptoms in diabetic patients could be tackled by using novel therapeutic approaches uncovered by these shared mechanisms. Understanding the comorbidity of depression in diabetic patients is essential to fully address T2DM pathophysiology and treatment. 10.1016/j.pnpbp.2021.110351
    A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer's Disease. Lynn Jessica,Park Mingi,Ogunwale Christiana,Acquaah-Mensah George K Journal of Alzheimer's disease : JAD Dementias, including the type associated with Alzheimer's disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as "type 3 diabetes". In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities. 10.3233/JAD-210612
    Downregulation of LRP1 [correction of LPR1] at the blood-brain barrier in streptozotocin-induced diabetic mice. Hong Hao,Liu Li Ping,Liao Jian Ming,Wang Tong Sheng,Ye Feng Ying,Wu Jing,Wang Ying Yu,Wang Ying,Li Yong Qi,Long Yan,Xia Yuan Zheng Neuropharmacology Deposition of amyloid-beta peptide (Abeta) in the diabetic brain is poorly understood. Low-density lipoprotein receptor related protein 1(LRP1) at the blood-brain barrier (BBB) is critical for regulation of Abeta homeostasis in the brain. In this study, we used streptozotocin-induced diabetic mice to observe the expression of LRP1 at the BBB by Western blot and immunocytochemical analysis, and to study in vivo brain-to-blood efflux transport of 125I-Abeta1-40 using brain clearance studies. In the diabetic mice with hyperglycemia (>16.0 mmol/l) at 6 weeks, LRP1 expression at the BBB was significantly downregulated; no significant changes of LRP1 levels were found at 1 and 3 weeks after diabetes induction. The data of brain clearance studies for Abeta showed significant decrease in LRP1-dependent transport of Abeta across the BBB at 6 weeks after diabetes induction, while no significant changes of LRP1-dependent transport of Abeta across the BBB at 1 or 3 weeks after diabetes induction were apparent. We conclude that the downregulation of LRP1 at the BBB contributes to cerebral Abeta deposition in diabetes mellitus. 10.1016/j.neuropharm.2009.03.001
    Spatiotemporal Dynamics of Cerebral Vascular Permeability in Type 2 Diabetes-Related Cerebral Microangiopathy. Chen Ying-Chen,Lu Bing-Ze,Shu Yu-Chen,Sun Yuan-Ting Frontiers in endocrinology Aims:Diabetes-related cerebral microangiopathy can manifest as cerebral small vessel disease (CSVD) and exhibit cognitive decline. To find the early change of function in advance, this study examined the spatiotemporal dynamics of cerebral vascular permeability () in the progression of type 2 diabetes mellitus (T2DM). Methods: was cross-sectionally measured in T2DM and non-diabetes groups with or without CSVD using dynamic contrast-enhanced MRI (DCE-MRI). Results:In all patients with T2DM, the of white matter (WM) was increased, whereas the of gray matter (GM) was increased only in T2DM with CSVD. The involvement of WM was earlier than GM and was before the CSVD features could be visualized on MRI. Among the commonly available four CSVD items of MRI, microbleeds were the most sensitive, indicating the increased permeability in all patients. Increased in T2DM was more associated with moderate WM hyperintensity but less with the presence of lacunae or multiple perivascular spaces, in contrast to patients without diabetes. The differential correlation suggested distinct mechanisms underlying diabetes-related CSVD and other CSVDs. Conclusions:This study highlights the early development of cerebral microangiopathy with increased BBB leakage in T2DM, before the CSVD features can be visualized on MRI. The results may increase the proactivity of clinicians in recognizing the subsequent neurological comorbidities. 10.3389/fendo.2021.805637
    Alterations in function and expression of ABC transporters at blood-brain barrier under diabetes and the clinical significances. Liu Li,Liu Xiao-Dong Frontiers in pharmacology Diabetes is a systematic metabolic disease, which often develops a number of well-recognized vascular complications including brain complications which may partly result from the dysfunction of blood-brain barrier (BBB). BBB is generally considered as a mechanism for protecting the brain from unwanted actions resulting from substances in the blood and maintaining brain homeostasis via monitoring the entry or efflux of compounds. ATP-binding cassette (ABC) family of transporters including P-glycoprotein (P-GP) and breast cancer-related protein (BCRP), widely expressed in the luminal membrane of the microvessel endothelium and in the apical membrane of the choroids plexus epithelium, play important roles in the function of BBB. However, these transporters are easily altered by some diseases. The present article was focused on the alteration in expression and function of both P-GP and BCRP at BBB by diabetes and the clinical significances. 10.3389/fphar.2014.00273
    Blood-Brain Barrier Disruption Induced Cognitive Impairment Is Associated With Increase of Inflammatory Cytokine. Geng Jieli,Wang Liping,Zhang Linyuan,Qin Chuan,Song Yaying,Ma Yuanyuan,Chen Yajing,Chen Shengdi,Wang Yongting,Zhang Zhijun,Yang Guo-Yuan Frontiers in aging neuroscience Patients with diabetes suffer the higher risk of dementia and the underlying pathological mechanism of cognitive dysfunction in diabetes is not fully understood. In this study, we explore whether the cognitive impairment in the diabetic rat is associated with increased blood brain barrier (BBB) permeability and the change of the inflammatory cytokine. Experimental diabetic rats were induced by single intraperitoneal injection of streptozotocin (STZ). Cognitive function was evaluated by Morris water maze in the normal and the diabetic rats, respectively. The spatial acquisition trials were conducted over five consecutive days and the probe test was performed on day 6, followed by working memory test on the next 4 days. Escape latency was recorded in the acquisition trials and working memory test; time spent in the target quadrant and the number of crossing the former platform were recorded in the probe test. BBB permeability was assessed by measuring the extravasation of IgG. The image of occludin and claudin-5 staining by a confocal microscope were acquired to measure the gap in the tight junction. Cytokines TNF-α, IL-1β and IL-6 mRNA expression were further examined by Real-time PCR. The time spent in the target quadrant within 30 s decreased in the 8-week STZ rats compared to that of the normal rats ( < 0.05), while no difference was seen in the performance of working memory between the diabetic and normal rats. IgG leakage significantly increased in the brain parenchyma of the 8-week STZ rats compared to the normal rats ( < 0.05). The immunostaining of occludin and claudin-5 suggested the gap in the tight junction increased in the 8-week STZ rats compared to the normal rats ( < 0.05). Moreover, TNF-α and IL-6 mRNA also increased in the brain of 8-week STZ rats compared to the normal rats ( < 0.05). These results suggested that loss of BBB integrity might contribute to progressive impairment of cognitive in the diabetic rats. The increase of TNF-α and IL-6 expression might trigger the disruption of BBB in the brain, which eventually caused cognitive impairment in the 8-week STZ rats. 10.3389/fnagi.2018.00129
    Diabetes aggravates heat stress-induced blood-brain barrier breakdown, reduction in cerebral blood flow, edema formation, and brain pathology: possible neuroprotection with growth hormone. Muresanu Dafin F,Sharma Aruna,Sharma Hari Shanker Annals of the New York Academy of Sciences The possibility that diabetes influences the outcome of heat stress-induced brain pathology was examined in our experimental rat model. Because growth hormone (GH) deficiency is an important factor in diabetes, the possible neuroprotective role of GH supplements was also examined in diabetic rats following heat stress. Rats receiving streptozotocine once daily for three days (50 mg/kg, i.p.) and allowed to survive four weeks resulted in diabetes (blood glucose level 18 and 20 mMol/L) compared to controls (blood glucose 4-6 mMol/L). Control or diabetic rats when subjected to four hours' heat stress at 38 degrees C in a biological oxygen demand incubator (BOD) showed profound disruption of the blood-brain barrier (BBB), reduction in cerebral blood flow (CBF), brain edema formation, and cell injury. These effects were most pronounced in diabetic rats. Pretreatment with GH (50 microg/kg/min for 10 min before heat stress) significantly attenuated brain pathology in normal animals subjected to hyperthermia. On the other hand, almost a double dose of the growth hormone (80 to 120 microg/g/min for 10 min) is needed in diabetic rats to induce considerable neuroprotection following heat stress. These observations are the first to suggest that diabetic rats are more vulnerable to heat stress-induced brain pathology and further show that the efficacy of neuroprotective drugs is also severely reduced in diabetic rats. Taken together, our results demonstrate that the dosage of neuroprotective drugs requires adjustment to enhance neuroprotection depending on the patient's endocrine or metabolic status, for example, diabetes mellitus, a finding not reported earlier. 10.1111/j.1749-6632.2009.05328.x
    Diabetes, cognitive function, and the blood-brain barrier. Huber J D Current pharmaceutical design From a complications standpoint, diabetes mellitus is a disease of the vasculature. Diabetics face a considerably higher risk of developing cardiovascular and cerebrovascular diseases. Both large and small blood vessels are susceptible to alterations from diabetes. Endothelial cell dysfunction associated with small vessel (known as microangiopathy) is a primary factor in the development and progression of diabetes-related disabilities, including blindness, kidney failure, and peripheral neuropathy. Recent clinical evidence show that people with diabetes have increased incidences of vascular dementia, ventricular hypertrophy, lacunar infarcts, hemorrhage, and may be a predisposing factor for Alzheimer's disease. However, the effects of diabetes mellitus on the cerebral microvascular are still largely unknown. This communication will review the relationship between diabetes mellitus and changes in cognition with a particular focus on how alterations in blood-brain barrier structure and function may play a long term role in worsened cognitive abilities.
    Peroxisome proliferator-activated receptor-γ activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier impairment and cognitive decline in type 2 diabetic mice. Min Li-Juan,Mogi Masaki,Shudou Masachika,Jing Fei,Tsukuda Kana,Ohshima Kousei,Iwanami Jun,Horiuchi Masatsugu Hypertension (Dallas, Tex. : 1979) We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-γ activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-γ activation to improve diabetes mellitus-induced cognitive decline. Type 2 diabetic mice KKA(y) exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-γ antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKA(y) mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKA(y) mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-γ activation by telmisartan may help with protection against cognitive decline by preserving the integrity of the BBB. 10.1161/HYPERTENSIONAHA.112.192401
    PPARγ agonists regulate bidirectional transport of amyloid-β across the blood-brain barrier and hippocampus plasticity in db/db mice. Wang Hao,Chen Fang,Zhong Kai Long,Tang Su Su,Hu Mei,Long Yan,Miao Ming Xing,Liao Jian Min,Sun Hong Bing,Hong Hao British journal of pharmacology BACKGROUND AND PURPOSE:There is emerging evidence suggesting that abnormal transport of amyloid-β (Aβ) across the blood-brain barrier (BBB) is involved in diabetes-associated cognitive decline. We investigated whether PPARγ agonists restore Aβ transport across the BBB and hippocampal plasticity in db/db mice. EXPERIMENTAL APPROACH:Efflux and influx of Aβ across the BBB were determined by stereotaxic intra-cerebral or i.a. infusion of [(125) I]-Aβ1-40 respectively. Receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1), which are involved in Aβ influx and efflux, PPARγ and NF-κB p65 at the BBB, as well as hippocampal Aβ, caspase-3, Bax and Bcl-2 were assayed by Western blot, immunohistochemistry and RT-PCR. In vivo, hippocampal LTP was recorded, and Morris water maze and Y-maze tasks were performed. KEY RESULTS:Treatment with PPARγ agonists, rosiglitazone (0.8 mg·kg(-1) ) and pioglitazone (9.0 mg·kg(-1) ), for 6 weeks significantly increased Aβ efflux and decreased Aβ influx across the BBB in db/db mice. Concomitantly, they decreased hippocampal Aβ1-40 and Aβ1-42 , suppressed neuronal apoptosis, as indicated by decreased caspase-3 activity and increased ratio of Bcl-2/Bax, and increased hippocampal plasticity, characterized by an enhanced in vivo LTP and better performance in behavioural tests. Furthermore, the PPARγ agonists induced the expression of LRP1 gene by activation of PPARγ and suppressed RAGE gene expression by inactivation of NF-κB signalling at the BBB of db/db mice. CONCLUSIONS AND IMPLICATIONS:PPARγ agonists modify abnormal Aβ transport across the BBB and this is accompanied by amelioration of β-amyloidosis and an improvement in hippocampal plasticity in diabetic mice. 10.1111/bph.13378
    Dysfunction of the neurovascular unit in diabetes-related neurodegeneration. Yan Caochong,Zhou Yunxiang,Chen Qiang,Luo Yi,Zhang John H,Huang Hefeng,Shao Anwen Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie In current aging societies, diabetes mellitus and neurodegenerative diseases represented by Alzheimer's disease are highly prevalent among adults, especially the elderly all over the world. It is worth noting that a substantial body of evidence suggests diabetes contributes to accelerated neurodegenerative processes and the decline of cognition. Over the last few years, some studies have indicated neurovascular uncoupling and disrupted functional connectivity in the early stages of many neurodegenerative diseases, and the concept of the neurovascular unit (NVU) has been highlighted to understand the initiation and progression of neurodegenerative diseases recently. Considering that some components of the NVU are also demonstrated to have abnormal morphology and function under the condition of diabetes, we propose the hypothesis that diabetes may promote the onset and development of neurodegenerative diseases by impairing the integrity of the NVU, named Diabetes-NVU-Neurodegeneration Hypothesis. The existing body of literature supporting the hypothesis and elucidating the underlying mechanisms will be summarized in this review. 10.1016/j.biopha.2020.110656
    Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models. Rom Slava,Zuluaga-Ramirez Viviana,Gajghate Sachin,Seliga Alecia,Winfield Malika,Heldt Nathan A,Kolpakov Mikhail A,Bashkirova Yulia V,Sabri Abdel Karim,Persidsky Yuri Molecular neurobiology End organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well-known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood-brain barrier (BBB) compromise plays a key role in cognitive decline in DM. Using a DM type 1 model (streptozotocin injected C57BL/6 mice) and type 2 model (leptin knockout obese db/db mice), we showed enhanced BBB permeability and memory loss (Y maze, water maze) that are associated with hyperglycemia. Gene profiling in isolated microvessels from DM type 1 animals demonstrated deregulated expression of 54 genes related to angiogenesis, inflammation, vasoconstriction/vasodilation, and platelet activation pathways by at least 2-fold (including eNOS, TNFα, TGFβ1, VCAM-1, E-selectin, several chemokines, and MMP9). Further, the magnitude of gene expression was linked to degree of cognitive decline in DM type 1 animals. Gene analysis in brain microvessels of DM type 2 db/db animals showed alterations of similar genes as in DM 1 model, some to an even greater extent. Neuropathologic analyses of brain tissue derived from DM mice showed microglial activation, expression of ICAM-1, and attenuated coverage of pericytes compared to controls. There was a significant upregulation of inflammatory genes in brain tissue in both DM models. Taken together, our findings indicate that BBB compromise in DM in vivo models and its association with memory deficits, gene alterations in brain endothelium, and neuroinflammation. Prevention of BBB injury may be a new therapeutic approach to prevent cognitive demise in DM. 10.1007/s12035-018-1195-5
    Antidiabetic drugs restore abnormal transport of amyloid-β across the blood-brain barrier and memory impairment in db/db mice. Chen Fang,Dong Rong Rong,Zhong Kai Long,Ghosh Arijit,Tang Su Su,Long Yan,Hu Mei,Miao Ming Xing,Liao Jian Min,Sun Hong Bing,Kong Ling Yi,Hong Hao Neuropharmacology Previous studies have shown significant changes in amyloid-β (Aβ) transport across the blood-brain barrier (BBB) under diabetic conditions with hypoinsulinemia, which is involved in diabetes-associated cognitive impairment. Present study employed db/db mice with hyperinsulinemia to investigate changes in Aβ transport across the BBB, hippocampal synaptic plasticity, and restorative effects of antidiabetic drugs. Our results showed that db/db mice exhibited similar changes in Aβ transport across the BBB to that of insulin-deficient mice. Chronic treatment of db/db mice with antidiabetic drugs such as metformin, glibenclamide and insulin glargine significantly decreased Aβ influx across the BBB determined by intra-arterial infusion of (125)I-Aβ(1-40), and expression of the receptor for advanced glycation end products (RAGE) participating in Aβ influx. Insulin glargine, but not, metformin or glibenclamide increased Aβ efflux across the BBB determined by stereotaxic intra-cerebral infusion of (125)I-Aβ(1-40), and expression of the low-density lipoprotein receptor related protein 1 (LRP1) participating in Aβ efflux. Moreover, treatment with these drugs significantly decreased hippocampal Aβ(1-40) or Aβ(1-42) and inhibited neuronal apoptosis. The drugs also ameliorated memory impairment confirmed by improved performance on behavioral tasks. However, insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing in vivo long-term potentiation (LTP). Further study found that these three drugs significantly restrained NF-κB, but only insulin glargine enhanced peroxisome proliferator-activated receptor γ (PPARγ) activity at the BBB in db/db mice. Our data indicate that the antidiabetic drugs can partially restore abnormal Aβ transport across the BBB and memory impairment under diabetic context. 10.1016/j.neuropharm.2015.07.023
    High-fat diet protects the blood-brain barrier in an Alzheimer's disease mouse model. Elhaik Goldman Shirin,Goez David,Last David,Naor Sharone,Liraz Zaltsman Sigal,Sharvit-Ginon Inbal,Atrakchi-Baranes Dana,Shemesh Chen,Twitto-Greenberg Rachel,Tsach Shoval,Lotan Roni,Leikin-Frenkel Alicia,Shish Aviv,Mardor Yael,Schnaider Beeri Michal,Cooper Itzik Aging cell Type 2 diabetes (T2D) is associated with increased risk of Alzheimer's disease (AD). There is evidence for impaired blood-brain barrier (BBB) in both diseases, but its role in the interplay between them is not clear. Here, we investigated the effects of high-fat diet (HFD), a model for T2D, on the Tg2576 mouse model of AD, in regard to BBB function. We showed that HFD mice had higher weight, more insulin resistance, and higher serum HDL cholesterol levels, primarily in Tg2576 mice, which also had higher brain lipids content. In terms of behavior, Tg2576 HFD mice were less active and more anxious, but had better learning in the Morris Water Maze compared to Tg2576 on regular diet. HFD had no effect on the level of amyloid beta 1-42 in the cortex of Tg2576 mice, but increased the transcription level of insulin receptor in the hippocampus. Tg2576 mice on regular diet demonstrated more BBB disruption at 8 and 12 months accompanied by larger lateral ventricles volume in contrast to Tg2576 HFD mice, whose BBB leakage and ventricular volume were similar to wild-type (WT) mice. Our results suggest that in AD, HFD may promote better cognitive function through improvements of BBB function and of brain atrophy but not of amyloid beta levels. Lipid metabolism in the CNS and peripheral tissues and brain insulin signaling may underlie this protection. 10.1111/acel.12818
    The blood-brain barrier as an endocrine tissue. Nature reviews. Endocrinology The blood-brain barrier (BBB) was first noted for its ability to prevent the unregulated exchange of substances between the blood and the central nervous system (CNS). Over time, its characterization as an interface that enables regulated exchanges between the CNS and substances that are carried in the blood in a hormone-like fashion have emerged. Therefore, communication between the CNS, BBB and peripheral tissues has many endocrine-like properties. In this Review, I examine the various ways in which the BBB exhibits endocrine-related properties. The BBB is a target for hormones, such as leptin and insulin, that affect many of its functions. The BBB is also a secretory body, releasing substances either into the blood or the interstitial fluid of the brain. The BBB selectively allows classical and non-classical hormones entry to and exit from the CNS, thus allowing the CNS to be both an endocrine target and a secretory tissue. The BBB is affected by endocrine diseases such as diabetes mellitus and can cause or participate in endocrine diseases, including those related to thyroid hormones and obesity. The endocrine-like mechanisms of the BBB can extend the definition of endocrine disease to include neurodegenerative conditions, including Alzheimer disease, and of hormones to include cytokines, triglycerides and fatty acids. 10.1038/s41574-019-0213-7
    Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview. Prasad Shikha,Sajja Ravi K,Naik Pooja,Cucullo Luca Journal of pharmacovigilance A host of diabetes-related insults to the central nervous system (CNS) have been clearly documented in type-1 and -2 diabetic patients as well as experimental animal models. These host of neurological disorders encompass hemodynamic impairments (e.g., stroke), vascular dementia, cognitive deficits (mild to moderate), as well as a number of neurochemical, electrophysiological and behavioral alterations. The underlying causes of diabetes-induced CNS complications are multifactorial and are relatively little understood although it is now evident that blood-brain barrier (BBB) damage plays a significant role in diabetes-dependent CNS disorders. Changes in plasma glucose levels (hyper- or hypoglycemia) have been associated with altered BBB transport functions (e.g., glucose, insulin, choline, amino acids, etc.), integrity (tight junction disruption), and oxidative stress in the CNS microcapillaries. Last two implicating a potential causal role for upregulation and activation of the receptor for advanced glycation end products (RAGE). This type I membrane-protein also transports amyloid-beta (Aβ) from the blood into the brain across the BBB thus, establishing a link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD, also referred to as "type 3 diabetes"). Hyperglycemia has been associated with progression of cerebral ischemia and the consequent enhancement of secondary brain injury. Difficulty in detecting vascular impairments in the large, heterogeneous brain microvascular bed and dissecting out the impact of hyper- and hypoglycemia has led to controversial results especially with regard to the effects of diabetes on BBB. In this article, we review the major findings and current knowledge with regard to the impact of diabetes on BBB integrity and function as well as specific brain microvascular effects of hyper- and hypoglycemia. 10.4172/2329-6887.1000125
    VEGF can protect against blood brain barrier dysfunction, dendritic spine loss and spatial memory impairment in an experimental model of diabetes. Taylor Stephanie L,Trudeau Dustin,Arnold Brendan,Wang Joshua,Gerrow Kim,Summerfeldt Kieran,Holmes Andrew,Zamani Akram,Brocardo Patricia S,Brown Craig E Neurobiology of disease Clinical and experimental studies have shown a clear link between diabetes, vascular dysfunction and cognitive impairment. However, the molecular underpinnings of this association remain unclear. Since vascular endothelial growth factor (VEGF) signaling is important for maintaining vascular integrity and function, we hypothesized that vascular and cognitive impairment in the diabetic brain could be related to a deficiency in VEGF signaling. Here we show that chronic hyperglycemia (~8weeks) in a mouse model of type 1 diabetes leads to a selective reduction in the expression of VEGF and its cognate receptor (VEGF-R2) in the hippocampus. Correlating with this, diabetic mice showed selective deficits in spatial memory in the Morris water maze, increased vessel area, width and permeability in the dentate gyrus/CA1 region of the hippocampus and reduced spine densities in CA1 neurons. Chronic low dose infusion of VEGF in diabetic mice was sufficient to restore VEGF signaling, protect them from memory deficits, as well as vascular and synaptic abnormalities in the hippocampus. These findings suggest that a hippocampal specific reduction in VEGF signaling and resultant vascular/neuronal defects may underlie early manifestations of cognitive impairment commonly associated with diabetes. Furthermore, restoring VEGF signaling may be a useful strategy for preserving hippocampal-related brain circuitry in degenerative vascular diseases. 10.1016/j.nbd.2015.03.022
    Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery. Patching Simon G Molecular neurobiology Glucose transporters (GLUTs) at the blood-brain barrier maintain the continuous high glucose and energy demands of the brain. They also act as therapeutic targets and provide routes of entry for drug delivery to the brain and central nervous system for treatment of neurological and neurovascular conditions and brain tumours. This article first describes the distribution, function and regulation of glucose transporters at the blood-brain barrier, the major ones being the sodium-independent facilitative transporters GLUT1 and GLUT3. Other GLUTs and sodium-dependent transporters (SGLTs) have also been identified at lower levels and under various physiological conditions. It then considers the effects on glucose transporter expression and distribution of hypoglycemia and hyperglycemia associated with diabetes and oxygen/glucose deprivation associated with cerebral ischemia. A reduction in glucose transporters at the blood-brain barrier that occurs before the onset of the main pathophysiological changes and symptoms of Alzheimer's disease is a potential causative effect in the vascular hypothesis of the disease. Mutations in glucose transporters, notably those identified in GLUT1 deficiency syndrome, and some recreational drug compounds also alter the expression and/or activity of glucose transporters at the blood-brain barrier. Approaches for drug delivery across the blood-brain barrier include the pro-drug strategy whereby drug molecules are conjugated to glucose transporter substrates or encapsulated in nano-enabled delivery systems (e.g. liposomes, micelles, nanoparticles) that are functionalised to target glucose transporters. Finally, the continuous development of blood-brain barrier in vitro models is important for studying glucose transporter function, effects of disease conditions and interactions with drugs and xenobiotics. 10.1007/s12035-015-9672-6
    Blood-Brain Barrier Disruption and Neurovascular Unit Dysfunction in Diabetic Mice: Protection with the Mitochondrial Carbonic Anhydrase Inhibitor Topiramate. Salameh Therese S,Shah Gul N,Price Tulin O,Hayden Melvin R,Banks William A The Journal of pharmacology and experimental therapeutics All forms of diabetes mellitus are characterized by chronic hyperglycemia, resulting in the development of a number of microvascular and macrovascular pathologies. Diabetes is also associated with changes in brain microvasculature, leading to dysfunction and ultimately disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. In diabetes, BBB damage is associated with increased oxidative stress and reactive oxygen species. This occurs because of the increased oxidative metabolism of glucose caused by hyperglycemia. Decreasing the production of bicarbonate with the use of a mitochondrial carbonic anhydrase inhibitor (mCAi) limits oxidative metabolism and the production of reactive oxygen species. In this study, we have demonstrated that 1) streptozotocin-induced diabetes resulted in BBB disruption, 2) ultrastructural studies showed a breakdown of the BBB and changes to the neurovascular unit (NVU), including a loss of brain pericytes and retraction of astrocytes, the two cell types that maintain the BBB, and 3) treatment with topiramate, a mCAi, attenuated the effects of diabetes on BBB disruption and ultrastructural changes in the neurovascular unit. 10.1124/jpet.116.237057
    Ginsenoside Rg1 nanoparticle penetrating the blood-brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction. Shen Junyi,Zhao Zhiming,Shang Wei,Liu Chunli,Zhang Beibei,Zhao Lingjie,Cai Hui International journal of nanomedicine Diabetic cerebral infarction is with poorer prognosis and high rates of mortality. Ginsenoside Rg1 (Rg1) has a wide variety of therapeutic values for central nervous system (CNS) diseases for the neuron protective effects. However, the blood-brain barrier (BBB) restricts Rg1 in reaching the CNS. In this study, we investigated the therapeutic effects of Rg1 nanoparticle (PHRO, fabricated with γ-PGA, L-PAE (H), Rg1, and OX26 antibody), targeting transferrin receptor, on the diabetes rats complicated with diabetic cerebral infarction in vitro and in vivo. Dynamic light scattering analysis shows the average particle size of PHRO was 79±18 nm and the polydispersity index =0.18. The transmission electron microscope images showed that all NPs were spherical in shape with diameters of 89±23 nm. PHRO released Rg1 with sustained release manner and could promote the migration of cerebrovascular endothelial cells and tube formation and even penetrated the BBB in vitro. PHRO could penetrate the BBB with high concentration in brain tissue to reduce the cerebral infarction volume and promote neuronal recovery in vivo. PHRO was promising to be a clinical treatment of diabetes mellitus with cerebral infarction. 10.2147/IJN.S139602
    Insulin transport across the blood-brain barrier can occur independently of the insulin receptor. Rhea Elizabeth M,Rask-Madsen Christian,Banks William A The Journal of physiology KEY POINTS:Insulin enters the brain from the blood via a saturable transport system. It is unclear how insulin is transported across the blood-brain barrier (BBB). Using two models of the signalling-related insulin receptor loss or inhibition, we show insulin transport can occur in vivo without the signalling-related insulin receptor. Insulin in the brain has multiple roles including acting as a metabolic regulator and improving memory. Understanding how insulin is transported across the BBB will aid in developing therapeutics to further increase CNS concentrations. ABSTRACT:A saturable system transports insulin from blood across the blood-brain barrier (BBB) and into the central nervous system. Whether or not the classic or signalling-related insulin receptor plays a role in mediating this transport in vivo is controversial. Here, we employed kinetics methods that distinguish between transport across the brain endothelial cell and reversible luminal surface receptor binding. Using a previously established line of mice with endothelial-specific loss of the signalling-related insulin receptor (EndoIRKO) or inhibiting the insulin receptor with the selective antagonist S961, we show insulin transport across the BBB is maintained. Rates of insulin transport were similar in all groups and transport was still saturable. Unlike transport, binding of insulin to the brain endothelial cell was decreased with the loss or inhibition of the signalling-related insulin receptor. These findings demonstrate that the signalling-related insulin receptor is not required for insulin transport across the BBB. 10.1113/JP276149
    Endothelial Adora2a Activation Promotes Blood-Brain Barrier Breakdown and Cognitive Impairment in Mice with Diet-Induced Insulin Resistance. Yamamoto Masaki,Guo De-Huang,Hernandez Caterina M,Stranahan Alexis M The Journal of neuroscience : the official journal of the Society for Neuroscience Obesity and insulin resistance elicit blood-brain barrier (BBB) breakdown in humans and animal models, but the relative contributions of the two pathologies remain poorly understood. These studies initially addressed the temporal progression of cerebrovascular dysfunction relative to dietary obesity or diet-induced insulin resistance in male mice. Obesity increased BBB permeability to the low molecular weight fluorophore sodium fluorescein (NaFl), whereas diet-induced insulin resistance increased permeability to both NaFl and Evans blue, which forms a high molecular weight complex with serum albumin. Serial section transmission electron microscopy analysis of hippocampal capillaries revealed that diabetes promotes involution of tight junctions, fenestration of endothelial cells, and pericyte regression. Chronic activation of adenosine receptor 2a (Adora2a) erodes tight junctions between endothelial cells of the cerebral vasculature in other models of chronic neuropathology, and we observed that acute Adora2a antagonism normalized BBB permeability in wild-type mice with diet-induced insulin resistance. Experiments in mice with inducible deletion of Adora2a in endothelial cells revealed protection against BBB breakdown with diet-induced insulin resistance, despite comparable metabolic dysfunction relative to nontransgenic littermates. Protection against BBB breakdown was associated with decreased vascular inflammation, recovery of hippocampal synaptic plasticity, and restoration of hippocampus-dependent memory. These findings indicate that Adora2a-mediated signaling in vascular endothelial cells disrupts the BBB in dietary obesity, and implicate cerebrovascular dysfunction as the underlying mechanism for deficits in synaptic plasticity and cognition with obesity and insulin resistance. The blood-brain barrier (BBB) restricts the entry of circulating factors into the brain, but obesity promotes BBB breakdown in humans and animal models. We used transgenic mice with resistance to BBB breakdown to investigate the role of neurovascular dysfunction in high-fat diet (HFD)-induced cognitive impairment. Transgenic mice with inducible ablation of Adora2a in endothelial cells were protected against BBB breakdown on HFD, despite comparable metabolic impairments relative to normal mice. Transgenic mice were also resistant to HFD-induced cognitive dysfunction and were protected against deficits in hippocampal synaptic plasticity. These findings indicate that Adora2a-mediated signaling in endothelial cells mediates obesity-induced BBB breakdown, and implicate cerebrovascular dysfunction as the mechanism for deficits in synaptic plasticity and cognition with obesity and diabetes. 10.1523/JNEUROSCI.2506-18.2019
    Severe Hypoglycemia Contributing to Cognitive Dysfunction in Diabetic Mice Is Associated With Pericyte and Blood-Brain Barrier Dysfunction. Lin Lu,Wu Yubin,Chen Zhou,Huang Lishan,Wang Lijing,Liu Libin Frontiers in aging neuroscience Severe hypoglycemia can cause cognitive impairment in diabetic patients, but the underlying molecular mechanism remains unclear. To assess the effect of severe hypoglycemia on cognitive function in diabetic mice to clarify the relationship between the mechanism and dysfunction of pericytes and the blood-brain barrier (BBB). We established type 1 diabetes mellitus in 80 male C57BL/6J mice by intraperitoneal injection of streptozotocin (150 mg/kg). Further intraperitoneal injection of short-acting insulin induced severe hypoglycemia. The mice were divided into normal, diabetes, and diabetic + severe hypoglycemia groups, and their blood glucose and general weight index were examined. Pericyte and BBB morphology and function were detected by histological and western blot analyses, BBB permeability was detected by Evans blue staining, and cognitive function was detected with the Morris water maze. Severe hypoglycemia aggravated the histological damage, BBB damage, brain edema, and pericyte loss in the diabetic mice. It also reduced the expression of the BBB tight junction proteins occludin and claudin-5, the expression of the pericyte-specific markers PDGFR-β (platelet-derived growth factor receptor-β) and α-SMA, and increased the expression of the inflammatory factor MMP9. At the same time, diabetic mice with severe hypoglycemia had significantly reduced cognitive function. Severe hypoglycemia leads to cognitive dysfunction in diabetic mice, and its possible mechanism is related to pericyte dysfunction and BBB destruction. 10.3389/fnagi.2021.775244
    HMGB1 signaling pathway in diabetes-related dementia: Blood-brain barrier breakdown, brain insulin resistance, and Aβ accumulation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Diabetes contributes to the onset of various diseases, including cancer and cardiovascular and neurodegenerative diseases. Recent studies have highlighted the similarities and relationship between diabetes and dementia as an important issue for treating diabetes-related cognitive deficits. Diabetes-related dementia exhibits several features, including blood-brain barrier disruption, brain insulin resistance, and Aβ over-accumulation. High-mobility group box1 (HMGB1) is a protein known to regulate gene transcription and cellular mechanisms by binding to DNA or chromatin via receptor for advanced glycation end-products (RAGE) and toll-like receptor 4 (TLR4). Recent studies have demonstrated that the interplay between HMGB1, RAGE, and TLR4 can impact both neuropathology and diabetic alterations. Herein, we review the recent research regarding the roles of HMGB1-RAGE-TLR4 axis in diabetes-related dementia from several perspectives and emphasize the importance of the influence of HMGB1 in diabetes-related dementia. 10.1016/j.biopha.2022.112933
    Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Janelidze Shorena,Hertze Joakim,Nägga Katarina,Nilsson Karin,Nilsson Christer, ,Wennström Malin,van Westen Danielle,Blennow Kaj,Zetterberg Henrik,Hansson Oskar Neurobiology of aging Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF biomarkers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage. 10.1016/j.neurobiolaging.2016.11.017
    Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition. Bogush Marina,Heldt Nathan A,Persidsky Yuri Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology Diabetes mellitus (DM) is a disorder due to the inability properly to metabolize glucose associated with dysregulation of metabolic pathways of lipids and proteins resulting in structural and functional changes of various organ systems. DM has detrimental effects on the vasculature, resulting in the development of various cardiovascular diseases and stemming from microvascular injury. The blood brain barrier (BBB) is a highly specialized structure protecting the unique microenvironment of the brain. Endothelial cells, connected by junctional complexes and expressing numerous transporters, constitute the main cell type in the BBB. Other components, including pericytes, basement membrane, astrocytes and perivascular macrophages, join endothelial cells to form the neurovascular unit (NVU) and contribute to the proper function and integrity of the BBB. The role of the BBB in the pathogenesis of diabetic encephalopathy and other diabetes-related complications in the central nervous system is apparent. However, the mechanisms, timing and consequences of BBB injury in diabetes are not well understood. The importance of further studies related to barrier dysfunction in diabetes is dictated by its potential involvement in the cognitive demise associated with DM. This review summarizes the impact of DM on BBB/NVU integrity and function leading to neurological and cognitive complications. 10.1007/s11481-017-9752-7
    Intracerebral Hemorrhage and Diabetes Mellitus: Blood-Brain Barrier Disruption, Pathophysiology and Cognitive Impairments. Bahadar Ghaith A,Shah Zahoor A CNS & neurological disorders drug targets There is a surge in diabetes incidence, with an estimated 463 million individuals been diagnosed worldwide. Diabetes Mellitus (DM) is a major stroke-related comorbid condition that increases the susceptibility of disabling post-stroke outcomes. Although less common, intracerebral hemorrhage (ICH) is the most dramatic subtype of stroke associated with higher mortality, particularly in the DM population. Previous studies have focused mainly on the impact of DM on ischemic stroke. Few studies have focused on the impact of DM on ICH and discussed the blood- -brain barrier disruption, brain edema, and hematoma formation. However, more recently, investigating the role of oxidative damage and Reactive Oxygen Species (ROS) production in preclinical studies involving DM-ICH animal models has gained attention. But, little is known about the correlation between neuroinflammatory processes, glial cells activation, and peripheral immune cell invasion with DM-ICH injury. DM and ICH patients experience impaired abilities in multiple cognitive domains by relatively comparable mechanisms, which could get exacerbated in the setting of comorbidities. In this review, we discuss both the pathology of DM as a comorbid condition for ICH and the potential molecular therapeutic targets for the clinical management of the ICH and its recovery. 10.2174/1871527320666210223145112
    Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues. Sheikh Madeeha H,Errede Mariella,d'Amati Antonio,Khan Noorafza Q,Fanti Silvia,Loiola Rodrigo A,McArthur Simon,Purvis Gareth S D,O'Riordan Caroline E,Ferorelli Davide,Dell'Erba Alessandro,Kieswich Julius,Reutelingsperger Chis,Maiorano Eugenio,Yaqoob Magdi,Thiemermann Christoph,Baragetti Andrea,Catapano Alberico Luigi,Norata Giuseppe Danilo,Marelli-Berg Federica,Virgintino Daniela,Solito Egle FASEB journal : official publication of the Federation of American Societies for Experimental Biology Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases. 10.1096/fj.202101297R
    Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes. Diabetes & metabolism journal As a structural barrier, the blood-brain barrier (BBB) is located at the interface between the brain parenchyma and blood, and modulates communication between the brain and blood microenvironment to maintain homeostasis. The BBB is composed of endothelial cells, basement membrane, pericytes, and astrocytic end feet. BBB impairment is a distinguishing and pathogenic factor in diabetic encephalopathy. Diabetes causes leakage of the BBB through downregulation of tight junction proteins, resulting in impaired functioning of endothelial cells, pericytes, astrocytes, microglia, nerve/glial antigen 2-glia, and oligodendrocytes. However, the temporal regulation, mechanisms of molecular and signaling pathways, and consequences of BBB impairment in diabetes are not well understood. Consequently, the efficacy of therapies diabetes targeting BBB leakage still lags behind the requirements. This review summarizes the recent research on the effects of diabetes on BBB composition and the potential roles of glial and vascular cells as therapeutic targets for BBB disruption in diabetic encephalopathy. 10.4093/dmj.2021.0146
    Irisin Exerts Neuroprotective Effects on Cultured Neurons by Regulating Astrocytes. Wang Kexin,Li Hongyan,Wang Hongxing,Wang Jun-Hui,Song Feng,Sun Yu Mediators of inflammation Neurons suffer detrimental effects from -amyloid toxicity in Alzheimer's disease. The exercise hormone, irisin, is found to induce a neuroprotective gene program and facilitates the beneficial effects on cognitive function. But no effort is made to test its direct protective effects on neurons against the A-induced cell toxicity so far. In the present study, we investigated whether irisin could protect neurons against A- (25-35) induced cell damage and explored the possible underlying mechanisms. Primary cell cultures of astrocytes and neurons were established. Conditioned medium from astrocyte was collected for the treatment and biochemistry assay study. To explore the protein expression changes, Western blot and ELISA assays were used in these cell culture models. Exposure of hippocampal neurons to 10 M A (25-35) caused significant reduction on cell viability, and the toxic effect was not significantly reduced by the coadministration of irisin. However, pretreated astrocyte-conditioned medium with irisin for 12 hours notably protected the neurons from the toxicity of A. Also, we found that irisin could attenuate the release of IL-6 and IL-1 from cultured astrocytes and decrease the expression level of COX-2 and phosphorylation of AKT. Last, we found that irisin could reduce NFB activation in astrocyte exposed to A by preventing the phosphorylation and the loss of IB. Our finding may provide novel evidence for the future application of irisin in the treatment of Alzheimer's disease and the memory dysfunction in diabetes mellitus. 10.1155/2018/9070341
    Novel therapeutic potential of angiotensin receptor 1 blockade in a rat model of diabetes-associated depression parallels altered BDNF signalling. Lenart Lilla,Balogh Dora B,Lenart Nikolett,Barczi Adrienn,Hosszu Adam,Farkas Tamas,Hodrea Judit,Szabo Attila J,Szigeti Krisztian,Denes Adam,Fekete Andrea Diabetologia AIMS/HYPOTHESIS:Diabetes is a worldwide epidemic linked with diverse diseases of the nervous system, including depression. A few studies suggested a connection between renin-angiotensin-aldosterone system blockers and reduced depressive symptoms, although underlying mechanisms are unclear. Here we investigated the antidepressant effect and the mechanisms of action of the angiotensin receptor 1 blocker (ARB) losartan in an experiential model of diabetes-associated depression. METHODS:Experimental diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated for 2 weeks with a non-pressor oral dose of losartan (20 mg/kg). In protocol 1, cerebrovascular perfusion and glial activation were evaluated by single-photon emission computed tomography-MRI and immunohistochemistry. In protocol 2, behaviour studies were performed (forced swim test and open field test). Hippocampal proinflammatory response and brain-derived neurotrophic factor (BDNF) signalling were also assessed. RESULTS:Here, we show that diabetic rats exhibit depression-like behaviour, which can be therapeutically reversed by losartan. This action of losartan occurs via changes in diabetes-induced neuroinflammatory responses rather than altered cerebral perfusion. We also show that as a part of its protective effect losartan restores BDNF production in astrocytes and facilitates BDNF-tropomyosin receptor kinase B-cAMP response element-binding protein signalling in the diabetic brain. CONCLUSIONS/INTERPRETATION:We identified a novel effect of losartan in the nervous system that may be implemented to alleviate symptoms of diabetes-associated depression. These findings explore a new therapeutic horizon for ARBs as possible antidepressants and suggest that BDNF could be a target of future drug development in diabetes-induced complications. 10.1007/s00125-019-4888-z
    Insulin regulates astrocyte gliotransmission and modulates behavior. Cai Weikang,Xue Chang,Sakaguchi Masaji,Konishi Masahiro,Shirazian Alireza,Ferris Heather A,Li Mengyao E,Yu Ruichao,Kleinridders Andre,Pothos Emmanuel N,Kahn C Ronald The Journal of clinical investigation Complications of diabetes affect tissues throughout the body, including the central nervous system. Epidemiological studies show that diabetic patients have an increased risk of depression, anxiety, age-related cognitive decline, and Alzheimer's disease. Mice lacking insulin receptor (IR) in the brain or on hypothalamic neurons display an array of metabolic abnormalities; however, the role of insulin action on astrocytes and neurobehaviors remains less well studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety- and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Munc18c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogs could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity, and other insulin-resistant states. 10.1172/JCI99366
    Berberine reduces neuroglia activation and inflammation in streptozotocin-induced diabetic mice. Liu Mei,Gao Linlin,Zhang Na International journal of immunopathology and pharmacology We aimed to analyze the action of berberine on the neuropathic pain and neuroglia activation in experimental diabetes mellitus (DM) model. Diabetes in mice was induced by intraperitoneal injection of streptozotocin (STZ) followed by the administration of berberine. Mechanical allodynia and thermal hyperalgesia and activations of microglia and astrocytes were evaluated. The levels of pro-inflammatory cytokines and protein expressions of inflammatory proteins were assessed by enzyme-linked immunosorbent assay (ELISA) and western blot, respectively. Our results revealed the anti-nociceptive effects of berberine in DM mice, supported by the improved mechanical threshold and thermal latency. In addition, berberine suppressed the activations of microglia and astrocytes in the spinal cords of diabetic mice. Berberine inhibited the expression of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and interleukin-1β (IL-1β), along with inflammatory proteins including iNOS and COX-2. Berberine suppressed neuropathic pain in STZ-induced diabetic mice, and this effect is related to the reduction on the neuroglia activation and inflammation associated with DM. 10.1177/2058738419866379
    The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity. Lorenzo Petra I,Martin Vazquez Eugenia,López-Noriega Livia,Fuente-Martín Esther,Mellado-Gil José M,Franco Jaime M,Cobo-Vuilleumier Nadia,Guerrero Martínez José A,Romero-Zerbo Silvana Y,Perez-Cabello Jesús A,Rivero Canalejo Sabrina,Campos-Caro Antonio,Lachaud Christian Claude,Crespo Barreda Alejandra,Aguilar-Diosdado Manuel,García Fuentes Eduardo,Martin-Montalvo Alejandro,Álvarez Dolado Manuel,Martin Franz,Rojo-Martinez Gemma,Pozo David,Bérmudez-Silva Francisco J,Comaills Valentine,Reyes José C,Gauthier Benoit R Theranostics We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated and in high-fat high-sucrose fed mice. We show that is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of and indicative of inflammation and reactive astrogliosis. transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce reactive astrogliosis in an attempt to preserve the neuronal network and re-establish glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote reactive astrogliosis and increase susceptibility of neurons to stress-induced apoptosis. Such effects could be reversed by ORY1001 treatment both and , paving the way for a new therapeutic approach for Type 2 Diabetes Mellitus. 10.7150/thno.57237
    Rosiglitazone up-regulates glial fibrillary acidic protein via HB-EGF secreted from astrocytes and neurons through PPARγ pathway and reduces apoptosis in high-fat diet-fed mice. Kushwaha Rajesh,Mishra Juhi,Gupta Anand Prakash,Gupta Keerti,Vishwakarma Jitendra,Chattopadhyay Naibedya,Gayen Jiaur Rahaman,Kamthan Mohan,Bandyopadhyay Sanghamitra Journal of neurochemistry The anti-diabetic drug and peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, rosiglitazone, alters astrocyte activation; however, its mechanism remains less-known. We hypothesized participation of epidermal growth factor receptor (EGFR), known to control astrocyte reactivity. We first detected that rosiglitazone promoted glial fibrillary acidic protein (GFAP) expression in primary astrocytes as well as the mouse cerebral cortex, associated with increased EGFR activation. Screening for EGFR ligands revealed a rosiglitazone-mediated increase of heparin-binding epidermal growth factor (HB-EGF) in astrocytes, resulting in HB-EGF release into culture medium and mouse cerebrospinal fluid too. Treatment with HB-EGF-siRNA and EGFR inhibitors showed that the rosiglitazone-induced HB-EGF and p-EFGR were interdependent, which participated in GFAP increase. Interestingly, we observed that rosiglitazone could induce cellular and secreted-HB-EGF in neurons also, contributing toward the activated EGFR-induced GFAP in astrocytes. Probing whether these effects of rosiglitazone were PPARγ-linked, revealed potential PPARγ-responsive elements within HB-EGF gene. Moreover, gel-shift, site-directed mutagenesis, chromatin-immunoprecipitation and luciferase-reporter assays demonstrated a PPARγ-dependent HB-EGF transactivation. Subsequently, we examined effects of rosiglitazone in a high-fat diet-fed diabetes mouse model, and supporting observations in the normal cortical cells, identified a rosiglitazone-induced GFAP, astrocyte and neuronal HB-EGF and secreted-HB-EGF in the cerebral cortex of diabetic mice. Moreover, assessing relevance of increased HB-EGF and GFAP revealed an anti-apoptotic role of rosiglitazone in the cerebral cortex, supported by a GFAP-siRNA as well as HB-EGF-siRNA-mediated increase in cleaved-caspase 3 and 9 levels in the rosiglitazone-treated astrocyte-neuron coculture. Overall, our study indicates that rosiglitazone may protect the brain, via a PPARγ-dependent HB-EGF/EGFR signaling and increased GFAP. 10.1111/jnc.14610
    Physiological and pathophysiological roles of hypothalamic astrocytes in metabolism. Chowen Julie A,Frago Laura M,Fernández-Alfonso María Soledad Journal of neuroendocrinology The role of glial cells, including astrocytes, in metabolic control has received increasing attention in recent years. Although the original interest in these macroglial cells was a result of astrogliosis being observed in the hypothalamus of diet-induced obese subjects, studies have also focused on how they participate in the physiological control of appetite and energy expenditure. Astrocytes express receptors for numerous hormones, growth factors and neuropeptides. Some functions of astrocytes include transport of nutrients and hormones from the circulation to the brain, storage of glycogen, participation in glucose sensing, synaptic plasticity, uptake and metabolism of neurotransmitters, release of substances to modify neurotransmission, and cytokine production, amongst others. In the hypothalamus, these physiological glial functions impact on neuronal circuits that control systemic metabolism to modify their outputs. The initial response of astrocytes to poor dietary habits and obesity involves activation of neuroprotective mechanisms but, with chronic exposure to these situations, hypothalamic astrocytes participate in the development of some of the damaging secondary effects. The present review discusses not only some of the physiological functions of hypothalamic astrocytes in metabolism, but also their role in the secondary complications of obesity, such as insulin resistance and cardiovascular affectations. 10.1111/jne.12671
    Physical exercise reverses spatial memory deficit and induces hippocampal astrocyte plasticity in diabetic rats. de Senna Priscylla Nunes,Bagatini Pamela Brambilla,Galland Fabiana,Bobermin Larissa,do Nascimento Patrícia Severo,Nardin Patrícia,Tramontina Ana Carolina,Gonçalves Carlos Alberto,Achaval Matilde,Xavier Léder Leal Brain research Physical exercise can induce brain plasticity and reduce the cognitive decline observed in type 1 diabetes mellitus (T1DM). We investigated the effects of physical exercise to prevent or reverse spatial memory deficits produced by diabetes and some biochemical and immunohistochemical changes in hippocampal astrocytes of T1DM model. In this study, 56 male Wistar rats were divided in four groups: trained control (TC), non-trained control (NTC), trained diabetic (TD) and non-trained diabetic (NTD). 27 days after streptozotocin-induced (STZ) diabetes, the exercise groups were submitted to 5 weeks of aerobic exercise. All groups were assessed in place recognition (PR) test before and after training. The glial fibrillary acidic protein (GFAP) positive astrocytes were evaluated using planar morphology, optical densitometry and Sholl's concentric circles method. Glucose and glutamate uptake, reduced glutathione (GSH) and glutamine synthetase (GS) levels were measured using biochemical assays. Our main results are: 1-Exercise reverses spatial memory impairments generated by T1DM; 2-Exercise increases GSH and GS in TC but not in TD rats; 3-Exercise increases density of GFAP positive astrocytes in the TC and TD groups and increases astrocytic ramification in TD animals. Our findings indicate that physical exercise reverses the cognitive deficits present in T1DM and induces important biochemical and immunohistochemical astrocytic changes. 10.1016/j.brainres.2016.10.024
    High glucose-induced complement component 3 up-regulation via RAGE-p38MAPK-NF-κB signalling in astrocytes: In vivo and in vitro studies. Zhao Yuxing,Luo Cheng,Chen Jinliang,Sun Yue,Pu Die,Lv Ankang,Zhu Shiyu,Wu Jing,Wang Meili,Zhou Jing,Liao Zhiyin,Zhao Kexiang,Xiao Qian Journal of cellular and molecular medicine Diabetes is considered as a risk for cognitive decline, which is characterized by neurodegenerative alteration and innate immunity activation. Recently, complement 3 (C3), the critical central component of complement system, has been reported to play a key role in neurodegenerative alterations under pathological condition. Receptor for advanced glycation end products (RAGE) activation is confirmed to mediate several inflammatory cytokines production. However, whether C3 activation participates in the diabetic neuropathology and whether this process is regulated by RAGE activation remains unknown. The present study aimed to investigate the role of C3 in streptozotocin-induced diabetic mice and high glucose-induced primary astrocytes and the underlying modulatory mechanisms. The decreased synaptophysin density and increased C3 deposition at synapses were observed in the diabetic brain compared to the control brain. Furthermore, the elevated C3 was co-localized with GFAP-positive astrocytes in the diabetic brain slice in vivo and high glucose-induced astrocytes culture in vitro. Diabetes/high glucose-induced up-regulation of C3 expression at gene, protein and secretion levels, which were attenuated by pre-treatment with RAGE, p38MAPK and NF-κB inhibitors separately. These results demonstrate that high glucose induces C3 up-regulation via RAGE- p38MAPK-NF-κB signalling in vivo and in vitro, which might be associated with synaptic protein loss. 10.1111/jcmm.13884
    Immunometabolic Changes in Glia - A Potential Role in the Pathophysiology of Obesity and Diabetes. Robb Josephine L,Morrissey Nicole A,Weightman Potter Paul G,Smithers Hannah E,Beall Craig,Ellacott Kate L J Neuroscience Chronic low-grade inflammation is a feature of the pathophysiology of obesity and diabetes in the CNS as well as peripheral tissues. Glial cells are critical mediators of the response to inflammation in the brain. Key features of glia include their metabolic flexibility, sensitivity to changes in the CNS microenvironment, and ability to rapidly adapt their function accordingly. They are specialised cells which cooperate to promote and preserve neuronal health, playing important roles in regulating the activity of neuronal networks across the brain during different life stages. Increasing evidence points to a role of glia, most notably astrocytes and microglia, in the systemic regulation of energy and glucose homeostasis in the course of normal physiological control and during disease. Inflammation is an energetically expensive process that requires adaptive changes in cellular metabolism and, in turn, metabolic intermediates can also have immunomodulatory actions. Such "immunometabolic" changes in peripheral immune cells have been implicated in contributing to disease pathology in obesity and diabetes. This review will discuss the evidence for a role of immunometabolic changes in glial cells in the systemic regulation of energy and glucose homeostasis, and how this changes in the context of obesity and diabetes. 10.1016/j.neuroscience.2019.10.021
    Astrocytic pyruvate dehydrogenase kinase-2 is involved in hypothalamic inflammation in mouse models of diabetes. Rahman Md Habibur,Bhusal Anup,Kim Jae-Hong,Jha Mithilesh Kumar,Song Gyun Jee,Go Younghoon,Jang Il-Sung,Lee In-Kyu,Suk Kyoungho Nature communications Hypothalamic inflammation plays an important role in disrupting feeding behavior and energy homeostasis as well as in the pathogenesis of obesity and diabetes. Here, we show that pyruvate dehydrogenase kinase (PDK)-2 plays a role in hypothalamic inflammation and its sequelae in mouse models of diabetes. Cell type-specific genetic ablation and pharmacological inhibition of PDK2 in hypothalamic astrocytes suggest that hypothalamic astrocytes are involved in the diabetic phenotype. We also show that the PDK2-lactic acid axis plays a regulatory role in the observed metabolic imbalance and hypothalamic inflammation in mouse primary astrocyte and organotypic cultures, through the AMPK signaling pathway and neuropeptidergic circuitry governing feeding behavior. Our findings reveal that PDK2 ablation or inhibition in mouse astrocytes attenuates diabetes-induced hypothalamic inflammation and subsequent alterations in feeding behavior. 10.1038/s41467-020-19576-1
    Fluorescein Permeability of the Blood-Brain Barrier Is Enhanced in Juvenile- but Not Young Adult-Onset Type 1 Diabetes in Rats. Tsuneoka Yayoi,Nishimura Tsubasa,Oka Jun-Ichiro Biological & pharmaceutical bulletin Clinically, neurological disorders, such as cognitive impairments and dementia, have been reported as diabetic complications, which are remarkable, especially in children with diabetes. The blood-brain barrier (BBB) is a physiologically dynamic regulatory barrier that maintains the consistency of the fluid microenvironment composition of the brain. However, the differences in BBB conditions between children and adults and the contribution of the BBB to the severity of cognitive impairments remain unclear. We generated adult-onset diabetes mellitus (DM) and juvenile-onset diabetes mellitus (JDM) diabetic rat models and investigated BBB functions in these models during the early stages of type 1 diabetes. We performed a BBB permeability assay using sodium fluorescein, a small-molecule fluorescent dye, to evaluate endothelial transport from the blood to the central nervous system. One week after diabetes onset, BBB permeability increased in the hippocampus and striatum of JDM rats, but no changes were observed in the frontal cortex and hypothalamus of JDM rats or for any region of DM rats. The double staining of tight junction proteins and astrocytes revealed no changes in the hippocampus and striatum of JDM rats. These results suggested that the observed increase in BBB permeability during early-stage diabetes onset in JDM rats, which did not depend on the expression of the interendothelial tight junction protein, claudin-5, may affect stylized neural development and cognitive function. 10.1248/bpb.b21-00248
    Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain. Bury Joanna J,Chambers Annabelle,Heath Paul R,Ince Paul G,Shaw Pamela J,Matthews Fiona E,Brayne Carol,Simpson Julie E,Wharton Stephen B, Acta neuropathologica communications Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P < 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention. 10.1186/s40478-020-01109-y
    Recurrent non-severe hypoglycemia aggravates cognitive decline in diabetes and induces mitochondrial dysfunction in cultured astrocytes. Gao Ruonan,Ren Lingjia,Zhou Yu,Wang Lijing,Xie Yunzhen,Zhang Mengjun,Liu Xiaoying,Ke Sujie,Wu Kejun,Zheng Jiaping,Liu Xiaohong,Chen Zhou,Liu Libin Molecular and cellular endocrinology The present study aimed to determine the relationship between astrocytes and recurrent non-severe hypoglycemia (RH) -associated cognitive decline in diabetes. RH induced cognitive impairment and neuronal cell death in the cerebral cortex of diabetic mice, accompanied by excessive activation of astrocytes. Levels of the neurotrophins BDNF and GDNF, together with BDNF and GDNF- related signaling, were downregulated by RH. In vitro, recurrent low glucose (RLG) impaired cell viability and induced apoptosis of high-glucose cultured astrocytes. Accumulating mitochondrial ROS and dysregulated mitochondrial functions, including abnormal morphology, decreased membrane potential, downregulated ATP levels, and disrupted bioenergetic status, were observed in these cells. SS-31 mediated protection of mitochondrial functions reversed RLG-induced cell viability defects and neurotrophin production. These findings demonstrate that RH induced astrocyte overactivation and mitochondrial dysfunction, leading to astrocyte-derived neurotrophin disturbance, which might contribute to diabetic cognitive decline. Targeting astrocyte mitochondria might represent a neuroprotective therapy for hypoglycemia-associated neurodegeneration in diabetes. 10.1016/j.mce.2021.111192
    Potential Glioprotective Strategies Against Diabetes-Induced Brain Toxicity. Sovrani Vanessa,Bobermin Larissa Daniele,Schmitz Izaviany,Leipnitz Guilhian,Quincozes-Santos André Neurotoxicity research Astrocytes are crucial for the maintenance of brain homeostasis by actively participating in the metabolism of glucose, which is the main energy substrate for the central nervous system (CNS), in addition to other supportive functions. More specifically, astrocytes support neurons through the metabolic coupling of synaptic activity and glucose utilization. As such, diabetes mellitus (DM) and consequent glucose metabolism disorders induce astrocyte damage, affecting CNS functionality. Glioprotective molecules can promote protection by improving glial functions and avoiding toxicity in different pathological conditions, including DM. Therefore, this review discusses specific pathomechanisms associated with DM/glucose metabolism disorder-induced gliotoxicity, namely astrocyte metabolism, redox homeostasis/mitochondrial activity, inflammation, and glial signaling pathways. Studies investigating natural products as potential glioprotective strategies against these deleterious effects of DM/glucose metabolism disorders are also reviewed herein. These products include carotenoids, catechins, isoflavones, lipoic acid, polysaccharides, resveratrol, and sulforaphane. 10.1007/s12640-021-00393-3