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    Peripheral inflammatory markers in Alzheimer's disease: a systematic review and meta-analysis of 175 studies. Lai Ka Sing P,Liu Celina S,Rau Allison,Lanctôt Krista L,Köhler Cristiano A,Pakosh Maureen,Carvalho André F,Herrmann Nathan Journal of neurology, neurosurgery, and psychiatry OBJECTIVES:Increasing evidence suggests that inflammation is involved in Alzheimer's disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC). METHODS:Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type. RESULTS:A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1β, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores. CONCLUSIONS:These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers. 10.1136/jnnp-2017-316201
    Association of leptin with orthostatic blood pressure changes in Parkinson's disease. Nakamura Tomohiko,Suzuki Masashi,Okada Akinori,Suzuki Junichiro,Hasegawa Satoru,Koike Haruki,Hirayama Masaaki,Katsuno Masahisa,Sobue Gen Movement disorders : official journal of the Movement Disorder Society INTRODUCTION:Leptin is involved in the regulation of blood pressure; however, no studies have evaluated the role of leptin in blood pressure changes during orthostatic stress in PD patients. The aim of this study was to determine whether plasma leptin levels influence orthostatic blood pressure changes in PD patients. METHODS:We enrolled 55 patients and 25 age-matched healthy controls in this study. Associations between head-up tilt test measurements and leptin levels were evaluated. RESULTS:Systolic blood pressure changes during the head-up tilt tests were strongly correlated with leptin levels at baseline and at a 60-degree head-up tilt in PD patients, but not in control subjects. Multiple regression analysis also demonstrated that leptin levels were associated with orthostatic blood pressure changes. CONCLUSION:These observations suggest that low leptin levels may be associated with orthostatic hypotension during the head-up tilt test in patients with PD. © 2016 International Parkinson and Movement Disorder Society. 10.1002/mds.26678
    Timing Matters: Circadian Effects on Energy Homeostasis and Alzheimer's Disease. Loehfelm Aline,Boucsein Alisa,Pretz Dominik,Tups Alexander Trends in endocrinology and metabolism: TEM Metabolic syndrome and Alzheimer's disease (AD) are two major health issues in modern society causing an extraordinary financial burden for the global healthcare systems. A tight link between the pathologies of obesity and type 2 diabetes (T2D), and more recently between T2D and AD, has been discovered. Furthermore, in recent years it has become apparent that the circadian clock has an important function in controlling metabolism. This review integrates the role of the circadian clock in the development of these metabolic derangements and vice versa. Common features such as central insulin resistance, altered glycogen synthase kinase 3β (GSK3β) signalling, and central inflammation are discussed, and therapeutic interventions targeting those mechanisms are mentioned briefly. 10.1016/j.tem.2018.12.001
    Microglia, neurodegeneration and loss of neuroendocrine control. Chowen Julie A,Garcia-Segura Luis M Progress in neurobiology Microglia, the primary regulators of inflammatory responses in the brain, suffer deterioration during aging culminating in their inability to generate adequate adaptive responses to maintain physiological homeostasis in brain tissue. Microglia affect the function of other glial cells and neurons, including those involved in the hypothalamic control of body homeostasis. Microglial dysfunction with aging in cognitive areas such as the hippocampus is known to associate with cognitive decline; more recently, microglial alterations in the hypothalamus during midlife was suggested to participate in changes in the endocrine and metabolic control exerted by this brain region. Consequently, the feed-back loops between endocrine glands and the hypothalamus are altered. This generates a vicious circle in which the plasma levels of key neuroprotective hormones, such as gonadal hormones, insulin-like growth factor-1, growth hormone and leptin and their hypothalamic signaling are decreased, which further enhances microglial alterations and deterioration of hypothalamic function. Hypothalamic dysfunction is a risk factor for neurodegenerative diseases and these diseases in turn promote additional alterations in hypothalamic microglial cells, which are unable to cope with the neurodegenerative process, resulting in permanent damage of the neuronal-glial circuits controlling endocrine homeostasis, food intake and body metabolism. Thus, a "vicious cycle" may such be initiated. 10.1016/j.pneurobio.2019.101720
    The blood-brain barrier as an endocrine tissue. Banks William A 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
    Sex-specific effects of central adiposity and inflammatory markers on limbic microstructure. Metzler-Baddeley Claudia,Mole Jilu P,Leonaviciute Erika,Sims Rebecca,Kidd Emma J,Ertefai Benyamin,Kelso-Mitchell Aurora,Gidney Florence,Fasano Fabrizio,Evans John,Jones Derek K,Baddeley Roland J NeuroImage Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38-71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and k] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and k, but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and k, whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD. 10.1016/j.neuroimage.2019.02.007
    Role of metabolism in neurodegenerative disorders. Procaccini Claudio,Santopaolo Marianna,Faicchia Deriggio,Colamatteo Alessandra,Formisano Luigi,de Candia Paola,Galgani Mario,De Rosa Veronica,Matarese Giuseppe Metabolism: clinical and experimental Along with the increase in life expectancy over the last century, the prevalence of age-related disorders, such as neurodegenerative diseases continues to rise. This is the case of Alzheimer's, Parkinson's, Huntington's diseases and Multiple sclerosis, which are chronic disorders characterized by neuronal loss in motor, sensory or cognitive systems. Accumulating evidence has suggested the presence of a strong correlation between metabolic changes and neurodegeneration. Indeed epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. In this context, hormones such as leptin, ghrelin, insulin and IGF-1 seem to play a key role in the regulation of neuronal damage, toxic insults and several other neurodegenerative processes. This review aims to presenting the most recent evidence supporting the crosstalk linking energy metabolism and neurodegeneration, and will focus on metabolic manipulation as a possible therapeutic tool in the prevention and treatment of neurodegenerative diseases. 10.1016/j.metabol.2016.05.018
    Glucocorticoid-mediated activation of GSK3β promotes tau phosphorylation and impairs memory in type 2 diabetes. Dey Aditi,Hao Shuai,Wosiski-Kuhn Marlena,Stranahan Alexis M Neurobiology of aging Type 2 diabetes is increasingly recognized as a risk factor for Alzheimer's disease, but the underlying mechanisms remain poorly understood. Hyperphosphorylation of the microtubule-associated protein tau has been reported in rodent models of diabetes, including db/db mice, which exhibit insulin resistance and chronically elevated glucocorticoids due to leptin receptor insufficiency. In this report, we investigated endocrine mechanisms for hippocampal tau phosphorylation in db/db and wild-type mice. By separately manipulating peripheral and intrahippocampal corticosterone levels, we determined that hippocampal corticosteroid exposure promotes tau phosphorylation and activates glycogen synthase kinase 3β (GSK3β). Subsequent experiments in hippocampal slice preparations revealed evidence for a nongenomic interaction between glucocorticoids and GSK3β. To examine whether GSK3β activation mediates tau phosphorylation and impairs memory in diabetes, db/db and wild-type mice received intrahippocampal infusions of TDZD-8, a non-ATP competitive thiadiazolidinone inhibitor of GSK3β. Intrahippocampal TDZD-8 blocked tau hyperphosphorylation and normalized hippocampus-dependent memory in db/db mice, suggesting that pathological synergy between diabetes and Alzheimer's disease may involve glucocorticoid-mediated activation of GSK3β. 10.1016/j.neurobiolaging.2017.05.010
    Leptin-Sensitive JAK2 Activation in the Regulation of Tau Phosphorylation in PC12 Cells. Guo Meixia,Li Dongliang,Shen Huijun,Jin Baijie,Ren Yankai,Li Manli,Xing Ying Neuro-Signals BACKGROUND/AIMS:Alzheimer's disease (AD) is characterized by two major hallmarks: the deposition and accumulation of β-amyloid (Aβ) peptide and hyperphosphorylated tau in intracellular neurofibrillary tangles. Sets of evidence show that leptin reduces Aβ production and tau phosphorylation. Herein, we investigated the signaling pathways activated by leptin, to extensively understand its mechanism. METHODS:Western blotting was employed to assess the protein abundance of p-tau and BAX, MTT assay to decipher the cells viability. RESULTS:Leptin decreased tau phosphorylation, an effect was dependent on the activation of JAK2. CONCLUSION:The data suggest that JAK2 is involved in AD-related pathways. 10.1159/000442615
    Leptin receptor deficiency induces early, transient and hyperglycaemia-independent blood-brain barrier dysfunction. Corem Noa,Anzi Shira,Gelb Sivan,Ben-Zvi Ayal Scientific reports Diabetes mellitus (DM) significantly increases susceptibility to central nervous system (CNS) pathologies, including stroke, vascular dementia, cognitive deficits and Alzheimer's disease. Previous studies (mostly using the streptozotocin model) suggested that blood-brain barrier (BBB) disruption is involved in these conditions. Here, we examined the integrity of brain capillaries and BBB permeability in Lepr obesity-related diabetic mice. Surprisingly, significant BBB leakage was observed only in young mice at the pre-hyperglycemic stage. Thorough examination of barrier permeability at later diabetic stages showed no evidence for significant BBB leakage during the hyperglycemic state. Electron microscopy imaging of mice with short-term hyperglycaemia supported normal BBB permeability but indicated other stress-related changes in capillary ultrastructure, such as mitochondrial degeneration. Based on our study with this mouse genetic model of obesity-related DM, we suggest that previously reported hyperglycaemia-induced BBB leakage is most likely not the underlying mechanism of DM-related CNS pathologies. Finally we propose that BBB hyper-permeability might be an early and transient phenomenon while stress-related endothelial pathologies do correlate with a short-term diabetic state. 10.1038/s41598-019-39230-1
    Leptin Regulates Tau Phosphorylation through Wnt Signaling Pathway in PC12 Cells. Zhang Zijuan,Guo Meixia,Zhang Juan,Du Caixia,Xing Ying Neuro-Signals BACKGROUND/AIMS:Leptin, an adipocytokine produced endogenously in the brain, is decreased in Alzheimer's disease(AD) and has also been shown to reduce Aβ levels in vitro and in vivo. Sets of evidence show that leptin reduces Aβ production and tau phosphorylation in neuronal cells and transgenic mice models of AD. Herein, we investigated the signaling pathway activated by leptin, to better understand its mechanism of action. METHODS:Western blotting was performed to assess the levels of phosphor-tau and Bax, RT-PCR to check the mRNA level of Bax. RESULTS:Leptin treatment significantly blunted Aβ-evoked tau phosphorylation and Bax levels, effects of which could be reversed by antagonist of Wnt signaling. CONCLUSION:The data indicate that Leptin may provide a novel therapeutic approach to AD treatment via wnt signaling. 10.1159/000442616
    Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer's Disease. Hölscher Christian Frontiers in aging neuroscience Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). The underlying mechanism that links up the two conditions seems to be the de-sensitization of insulin signaling. In patients with AD, insulin signaling was found to be de-sensitized in the brain, even if they did not have diabetes. Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common - they induce a chronic inflammation response in the brain. Pro-inflammatory cytokines block growth factor signaling and enhance oxidative stress. The underlying molecular processes for this are described in the review. Treatments to re-sensitize insulin signaling in the brain are also described, such as nasal insulin tests in AD patients, or treatments with re-sensitizing hormones, such as leptin, ghrelin, glucagon-like peptide 1 (GLP-1),and glucose-dependent insulinotropic polypeptide (GIP). The first clinical trials show promising results and are a proof of concept that utilizing such treatments is valid. 10.3389/fnagi.2019.00088
    Effects of Leptin on Na+/Ca2+ Exchanger in PC12 Cells. Zhang Zijuan,Sun Shuguang,Du Caixia,Li Wei,Zhang Juan,Zhu Yanqin,Liu Peilin,Xing Ying Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:Alzheimer's disease (AD) is known to be related to alterations in neuronal intracellular calcium activity ([Ca2+]i). The present study revealed the distinct role of leptin in Na+/Ca2+-exchanger activity. METHODS:[Ca2+]i was determined utilizing Fura-2 fluorescence. The activity of NCX was measured by removal of extracellular Na+ in the presence of external Ca2+. Na+/Ca2+-exchanger activity was further quantified from whole cell currents following removal of extracellular Na+. Na+/Ca2+-exchanger isoform NCX1 transcript levels and protein abundance were quantified by RT-PCR and Western blotting, respectively. RESULTS:Exposure of PC12 cells to 30 µM amyloid (Aβ42) increased [Ca2+]i, an effect significantly blunted by 6 hours incubation with leptin before Aβ42 treatment. Moreover, leptin treatment significantly increased Na+/Ca2+-exchanger mediated Ca+ transport and current, NCX1 transcript level as well as NCX1 membrane protein abundance. CONCLUSION:We show that leptin blunts Aβ42-evoked [Ca2+]i increase by increasing expression and activity of Na+/Ca2+-exchanger NCX1. 10.1159/000453203
    Chronic cerebral hypoperfusion upregulates leptin receptor expression in astrocytes and tau phosphorylation in tau transgenic mice. Shimada Takuya,Shindo Akihiro,Matsuyama Hirofumi,Yata Kenichiro,Niwa Atsushi,Sasaki Ryogen,Ayaki Takashi,Maki Takakuni,Wakita Hideaki,Tomimoto Hidekazu Neuroscience letters Alzheimer's disease (AD) is the most common type of dementia in aging adults. Increasing evidence has revealed that vascular risk factors influence the midlife development of AD and that diet-induced obesity accelerates tau phosphorylation in tau transgenic mice and increases the level of serum leptin receptor (leptin-R). Leptin-R is upregulated in the peri-infarct cortices after acute cerebral ischemia. Leptin may be protective against the development of AD as it can inactivate GSK-3β through the phosphorylation of Ser-9, leading to the reduction of tau phosphorylation. Using tau transgenic mice, the present study examined whether chronic cerebral hypoperfusion affects leptin-R signaling and tau phosphorylation. Eight-month-old tau transgenic mice (T44) overexpressing the shortest human tau isoform were subjected to chronic cerebral hypoperfusion with bilateral common carotid artery stenosis (BCAS) using microcoils or sham surgery. Their brains were analyzed four weeks later to evaluate the expression of phosphorylated tau and leptin-R via immunohistochemistry and Western blot analysis. In addition, expression of leptin-R was examined in the rat primary astrocyte cultures subjected to prolonged chemical hypoxic stress, as well as in autopsied brains. BCAS upregulated leptin-R expression and promoted the expression of phosphorylated tau in T44 Tg mice. In primary astrocyte cultures, leptin-R was upregulated under hypoxic conditions via the phosphorylated AKT/pAKT pathway, possibly suppressing the expression of caspase 3. Leptin-R was also strongly expressed in autopsied brains with AD and cerebrovascular diseases. These results collectively indicate that chronic cerebral hypoperfusion promotes leptin-R signaling and tau phosphorylation. 10.1016/j.neulet.2019.04.009
    Does plasma phoenixin level associate with cognition? Comparison between subjective memory complaint, mild cognitive impairment, and mild Alzheimer's disease. Yuruyen Mehmet,Gultekin Gozde,Batun Gizem Cetiner,Yavuzer Hakan,Akcan Fundan Engin,Doventas Alper,Emul Murat International psychogeriatrics BACKGROUND:Alteration in energy expenditure or metabolism is the most accused risk issue for the onset and for the course of neurodegenerative cognitive disorders. Neuropeptides are suggested to be related with learning and memory. Phoenixin (PNX) is the most recently reported neuropeptide and we aimed to compare the plasma level in people with subjective memory complaints, patients with mild cognitive impairment, and mild Alzheimer's disease (AD). METHODS:Ninety two participants enrolled in the study. After screening tests, all participants were assessed with a neuropsychological battery for further cognitive evaluations. We used ELISA kit to assay the level of Human PNX. RESULTS:Patients with AD were significantly older than people in subjective memory complaint group (p = 0.02). There was no significant difference between groups according to gender (p = 0.435). Mean plasma PNX level was not significantly different between groups (p = 0.279). Mean plasma PNX level in MCI group was positively correlated with BMI (r = 0.402 and p = 0.028), serum HDL level (r = 0.454 and p = 0.012), blood systolic pressure (r = 0.428 and p = 0.018) and negatively correlated with logical memory (r=-0.335 and p=0.031). The mean plasma PNX level was positively correlated with immediate recall in subjective memory complaint group (r = 0.417 and p = 0.034). CONCLUSION:This study is the first studying the association of plasma PNX level and cognitive complaints or decline. The knowledge about the role, interaction, and physiological functions of PNX is lacking. Lower plasma PNX level might be important in prodromal stages as MCI and the predictive role of PNX should be investigated in further studies. 10.1017/S1041610217000825
    Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice. Meakin Paul J,Jalicy Susan M,Montagut Gemma,Allsop David J P,Cavellini Daniella L,Irvine Stuart W,McGinley Christopher,Liddell Mary K,McNeilly Alison D,Parmionova Karolina,Liu Yu-Ru,Bailey Charlotte L S,Dale J Kim,Heisler Lora K,McCrimmon Rory J,Ashford Michael L J Scientific reports Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central Aβ levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated Aβ promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer's disease, may be useful agents for the treatment of obesity and associated diabetes. 10.1038/s41598-017-18388-6
    Leptin Regulation of Synaptic Function at Hippocampal TA-CA1 and SC-CA1 Synapses: Implications for Health and Disease. McGregor Gemma,Harvey Jenni Neurochemical research Growing evidence indicates that the endocrine hormone leptin regulates hippocampal synaptic function in addition to its established role as a hypothalamic satiety signal. Indeed, numerous studies show that leptin facilitates the cellular events that underlie hippocampal learning and memory including activity-dependent synaptic plasticity and glutamate receptor trafficking, indicating that leptin may be a potential cognitive enhancer. Although there has been extensive investigation into the modulatory role of leptin at hippocampal Schaffer collateral (SC)-CA1 synapses, recent evidence indicates that leptin also potently regulates excitatory synaptic transmission at the anatomically distinct temporoammonic (TA) input to hippocampal CA1 neurons. The cellular mechanisms underlying activity-dependent synaptic plasticity at TA-CA1 synapses differ from those at SC-CA1 synapses and the TA input is implicated in spatial and episodic memory formation. Furthermore, the TA input is an early target for neurodegeneration in Alzheimer's disease (AD) and aberrant leptin function is linked to AD. Here, we review the evidence that leptin regulates hippocampal synaptic function at both SC- and TA-CA1 synapses and discuss the consequences for neurodegenerative disorders like AD. 10.1007/s11064-017-2362-1
    Down Syndrome, Obesity, Alzheimer's Disease, and Cancer: A Brief Review and Hypothesis. Nixon Daniel W Brain sciences Down syndrome (trisomy 21), a complex mix of physical, mental, and biochemical issues, includes an increased risk of Alzheimer's disease and childhood leukemia, a decreased risk of other tumors, and a high frequency of overweight/obesity. Certain features related to the third copy of chromosome 21 (which carries the APP gene and several anti-angiogenesis genes) create an environment favorable for Alzheimer's disease and unfavorable for cancer. This environment may be enhanced by two bioactive compounds from fat cells, leptin, and adiponectin. This paper outlines these fat-related disease mechanisms and suggests new avenues of research to reduce disease risk in Down syndrome. 10.3390/brainsci8040053
    Association of adiponectin, leptin and resistin with inflammatory markers and obesity in dementia. Bednarska-Makaruk Małgorzata,Graban Ałła,Wiśniewska Anna,Łojkowska Wanda,Bochyńska Anna,Gugała-Iwaniuk Magdalena,Sławińska Ksenia,Ługowska Agnieszka,Ryglewicz Danuta,Wehr Hanna Biogerontology The aim of the study was to determine the role of adiponectin, leptin and resistin in various types of dementia and to investigate their association with inflammatory markers, insulin resistance and abdominal obesity. In 205 patients with dementia [89 with Alzheimer's disease (AD), 47 with vascular dementia (VaD), 69 with mixed dementia (MD)], 113 persons with mild cognitive impairment and in 107 controls serum adiponectin, leptin and resistin levels, pro-inflammatory [interleukin-6 (IL-6), C-reactive protein (hsCRP) and chitotriosidase] and anti-inflammatory (25-OH vitamin D, HDL-cholesterol and paraoxonase 1) markers, as well as glucose metabolism parameters (glucose, insulin and HOMA-IR) were determined. In all-cause dementia adiponectin and resistin levels were significantly higher as compared to the controls; leptin levels did not show differences. Higher adiponectin levels concerned AD and MD, whereas higher resistin-VaD and MD. After stratification by abdominal obesity the differences in adiponectin levels remained significant in subjects without obesity. In all-cause dementia negative correlation of adiponectin with obesity, glucose metabolism parameters, IL-6 and hsCRP and positive correlation with HDL-cholesterol were found. Positive correlation of resistin with age, IL-6, hsCRP and chitotriosidase and negative correlation with HDL-cholesterol and paraoxonase 1 were stated. We conclude that dementia of neurodegenerative origin is characterized by elevated adiponectin levels, whereas dementia with vascular changes by increase of resistin. Association with inflammatory indicators may suggest the pro-inflammatory role of resistin in the development of dementia, especially in dementia of vascular mechanism. Identification of this novel biomarker may be important in preventing dementia. 10.1007/s10522-017-9701-0
    Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer's disease. Fernandez-Martos Carmen M,Atkinson Rachel A K,Chuah Meng I,King Anna E,Vickers James C Alzheimer's & dementia (New York, N. Y.) INTRODUCTION:Combination therapy approaches may be necessary to address the many facets of pathologic change in the brain in Alzheimer's disease (AD). The drugs leptin and pioglitazone have previously been shown individually to have neuroprotective and anti-inflammatory actions, respectively, in animal models. METHODS:We studied the impact of combined leptin and pioglitazone treatment in 6-month-old APP/PS1 (APPswe/PSEN1dE9) transgenic AD mouse model. RESULTS:We report that an acute 2-week treatment with combined leptin and pioglitazone resulted in a reduction of spatial memory deficits (Y maze) and brain β-amyloid levels (soluble β-amyloid and amyloid plaque burden) relative to vehicle-treated animals. Combination treatment was also associated with amelioration in plaque-associated neuritic pathology and synapse loss, and also a significantly reduced neocortical glial response. DISCUSSION:Combination therapy with leptin and pioglitazone ameliorates pathologic changes in APP/PS1 mice and may represent a potential treatment approach for AD. 10.1016/j.trci.2016.11.002
    Association between Peripheral Leptin and Adiponectin Levels and Cognitive Decline in Patients with Neurocognitive Disorders ≥65 Years. Gilbert Thomas,Roche Sylvain,Blond Emilie,Bar Jean-Yves,Drai Jocelyne,Cuerq Charlotte,Haution-Bitker Marine,Ecochard René,Bonnefoy Marc Journal of Alzheimer's disease : JAD BACKGROUND:There is evidence that adipokines have roles in brain functioning and cognitive decline. OBJECTIVE:Assess the role of leptin and adiponectin levels in predicting changes in neuro-cognitive disorders (NCD). METHODS:The study included 205 patients over 65 years of age presenting for a one-day hospitalization for current assessment of cognitive function. Peripheral blood leptin and adiponectin levels were measured at admission. Demographic variables, body mass index (BMI), and history of hypertension were also recorded. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at admission and at later scheduled visits over a median follow-up period of 14.5 months. Conventional univariate comparisons were made between diagnosis groups (Alzheimer's disease (AD), mild NCD, vascular/mixed dementia). Changes in MMSE scores over time were examined with regard to the above variables using a linear mixed model. RESULTS:The mean BMI was significantly lower (by 2 kg/m2, p = 0.01) in patients with AD than in patients with either mild-NCD or vascular/mixed dementia. Leptin levels were significantly higher (p = 0.043) and adiponectin levels significantly lower (p = 0.045) in patients with mild-NCD than in patients with major-NCD (AD or vascular/mixed dementia). However, the mixed model suggested no influence of the baseline levels of these two biomarkers on the course of cognitive decline. CONCLUSION:The present study confirms the associations between leptin and adiponectin and AD or AD-related disorders but did not confirm that these peptides may be used as predictive biomarkers of cognitive decline. 10.3233/JAD-180533
    Early-Stage Alzheimer's Disease Is Associated with Simultaneous Systemic and Central Nervous System Dysregulation of Insulin-Linked Metabolic Pathways. de la Monte Suzanne M,Tong Ming,Daiello Lori A,Ott Brian R Journal of Alzheimer's disease : JAD BACKGROUND:Brain insulin resistance is a well-recognized abnormality in Alzheimer's disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity. OBJECTIVE:This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related. METHODS:Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and 21 controls using a multiplex ELISA platform. RESULTS:In MCI/AD, both the CSF and serum samples had significantly elevated mean levels of C-peptide and an incretin, and reduced expression of Visfatin, whereas only CSF showed significant reductions in insulin and leptin and only serum had increased glucagon, PAI-1, and ghrelin. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different. CONCLUSION:In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors. 10.3233/JAD-180906
    Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation. Lee Yi-Heng,Hsu Hao-Chieh,Kao Pei-Chen,Shiao Young-Ji,Yeh Skye Hsin-Hsien,Shie Feng-Shiun,Hsu Shu-Meng,Yeh Chih-Wen,Liu Hui-Kang,Yang Shi-Bing,Tsay Huey-Jen International journal of molecular sciences Alzheimer's disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [F]-2-fluoro-2-deoxy-d-glucose ([F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aβ and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis. 10.3390/ijms19082333
    Chronic diabetic states worsen Alzheimer neuropathology and cognitive deficits accompanying disruption of calcium signaling in leptin-deficient APP/PS1 mice. Zhang Shuai,Chai Rui,Yang Ying-Ying,Guo Shi-Qi,Wang Shan,Guo Tian,Xu Shuang-Feng,Zhang Yan-Hui,Wang Zhan-You,Guo Chuang Oncotarget The coincidences between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are so compelling that it is attractive to speculate that diabetic conditions might aggravate AD pathologies by calcium dysfunction, although the understanding of the molecular mechanisms involved remains elusive. The present work was undertaken to investigate whether calcium dyshomeostasis is associated with the exacerbated Alzheimer-like cognitive dysfunction observed in diabetic conditions in APP/PS1-ob/ob mice, which were generated by crossing ob/ob mice with APP/PS1 mice. We confirmed that the diabetic condition can aggravate not only Aβ deposition but also tau phosphorylation, synaptic loss, neuronal death, and inflammation, exacerbating cognitive impairment in AD mice. More importantly, we found that the diabetic condition dramatically elevated calcium levels in APP/PS1 mice, thereby stimulating the phosphorylation of the calcium-dependent kinases. Our findings suggest that controlling over-elevation of intracellular calcium may provide novel insights for approaching AD in diabetic patients and delaying AD progression. 10.18632/oncotarget.17116
    Consequences of Metabolic Disruption in Alzheimer's Disease Pathology. Ryu J C,Zimmer E R,Rosa-Neto P,Yoon S O Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Alzheimer's disease (AD) is an irreversible, progressive disease that slowly destroys cognitive function, such as thinking, remembering, and reasoning, to a level that one cannot carry out a daily living. As people live longer, the risk of developing AD has increased to 1 in 10 among people who are older than 65 and to almost 1 in 2 among those who are older than 85 according to a 2019 Alzheimer's Association report. As a most common cause of dementia, AD accounts for 60-80% of all dementia cases. AD is characterized by amyloid plaques and neurofibrillary tangles, composed of extracellular aggregates of amyloid-β peptides and intracellular aggregates of hyperphosphorylated tau, respectively. Besides plaques and tangles, AD pathology includes synaptic dysfunction including loss of synapses, inflammation, brain atrophy, and brain hypometabolism, all of which contribute to progressive cognitive decline. Recent genetic studies of sporadic cases of AD have identified a score of risk factors, as reported by Hollingworth et al. (Nat Genet 43:429-435, 2001) and Lambert et al. (Nat Genet 45:1452-1458, 2013). Of all these genes, apolipoprotein E4 (APOE4) still presents the biggest risk factor for sporadic cases of AD, as stated in Saunders et al. (Neurology 43:1467-1472, 1993): depending on whether you have 1 or 2 copies of APOE4 allele, the risk increases from 3- to 12-fold, respectively, in line with Genin et al. (Mol Psychiatry 16:903-907, 2011). Besides these genetic risk factors, having type 2 diabetes (T2D), a chronic metabolic disease, is known to increase the AD risk by at least 2-fold when these individuals age, conforming to Sims-Robinson et al. (Nat Rev Neurol 6:551-559, 2010). Diabetes is reaching a pandemic scale with over 422 million people diagnosed worldwide in 2014 according to World Health Organization. Although what proportion of these diabetic patients develop AD is not known, even if 10% of diabetic patients develop AD later in their life, it would double the number of AD patients in the world. Better understanding between T2D and AD is of paramount of importance for the future. The goal of this review is to examine our current understanding on metabolic dysfunction in AD, so that a potential target can be identified in the near future. 10.1007/s13311-019-00755-y
    The impact of anorexigenic peptides in experimental models of Alzheimer's disease pathology. Maletínská Lenka,Popelová Andrea,Železná Blanka,Bencze Michal,Kuneš Jaroslav The Journal of endocrinology Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD. 10.1530/JOE-18-0532
    The Inverse Relationship Between Cancer and Alzheimer's Disease: A Possible Mechanism. Nixon Daniel W Current Alzheimer research BACKGROUND:Cancer and Alzheimer's disease (AD) are both associated with aging, but do not often occur together. Obesity is a shared risk factor for both diseases and may be involved in this curious clinical observation. Fat cells produce many active substances, including leptin and adiponectin; leptin has cancer stimulating and AD inhibiting properties, while adiponectin can inhibit cancer but stimulate AD. OBJECTIVE:To describe the opposing effects of leptin and adiponectin on cancer and AD, to outline signaling pathways involved in these effects and to suggest new research on effective control strategies for both diseases. METHODS:A review was conducted to document the inverse cancer/AD relationship and the role of excess body fat as a common risk factor. Previous studies have suggested the involvement of p53, Wnt and other cell signaling pathways in this inverse relationship. The opposing effects of leptin and adiponectin on these signaling pathways in cancer and AD were evaluated. RESULTS:The inverse cancer/AD relationship is well documented, as is the role of excess body fat, especially central obesity, in increasing risk for both diseases. Leptin and adiponectin have opposing effects in cancer and AD mediated by signaling factors that influence apoptosis, angiogenesis, and other cell growth controls. Wnt and p53 are prominent among these signaling factors. CONCLUSION:Opposing effects of leptin and adiponectin, mediated by specific cell signaling pathways, are involved in the inverse cancer/Ad relationship. Future research aimed at modifying the leptin/adiponectin ratio may lead to important treatment and control approaches in both cancer and AD. 10.2174/1567205014666170216152905
    The cause-effect relationship between bone loss and Alzheimer's disease using statistical modeling. Loskutova Natalia,Watts Amber S,Burns Jeffrey M Medical hypotheses BACKGROUND:Animal studies provide strong evidence that the CNS directly regulates bone remodeling through the actions of the hypothalamus via two distinct pathways, the neural (mediated by leptin) arm and neurohumoral (mediated by neurohormones and growth factors) arm. The impact of AD on central regulatory mechanisms of bone mass is not known. OBJECTIVES:To test a model that assesses the relationship between hypothalamic atrophy and bone loss in Alzheimer's disease (AD) and potential mediation through neural (leptin) and neurohumoral (insulin-like growth factor -1, IGF-1) mechanisms. HYPOTHESES:AD-related hypothalamic structural change alters neural and neurohumoral regulatory systems of bone remodeling and contributes to bone loss in early AD. DESIGN:A secondary data analysis of data obtained in a two-year longitudinal study with path analysis and longitudinal mediation modeling. PARTICIPANTS:The data were collected as a part of the University of Kansas Brain Aging Project, a two-year observational study of 71 older adults with early stage AD and 69 non-demented controls. MEASUREMENTS:Demographic characteristics and measures of bone density, body composition, and hypothalamic volume, serum levels of leptin, growth hormone, and IGF-1 were collected. RESULTS:Hypothalamic atrophy and bone loss were observed in AD group and were associated. Data modeling suggests that bone loss may precede measurable changes in the brain. Leptin increased over two years in AD and the increase in leptin was associated with hypothalamic atrophy. However, changes in leptin or IGF-1 levels did not mediate the relationship between hypothalamic atrophy and bone loss. CONCLUSIONS:This study extends previous findings by suggesting that bone loss in AD may be related to neurodegenerative changes (atrophy) in the hypothalamus. Further studies are needed to explore the role of brain atrophy and mediating mechanisms in bone loss. Further exploring temporal relationship between bone loss and AD may have an important diagnostic value. 10.1016/j.mehy.2018.10.024
    The therapeutic potential of metabolic hormones in the treatment of age-related cognitive decline and Alzheimer's disease. Grizzanti John,Lee Hyoung-Gon,Camins Antoni,Pallas Merce,Casadesus Gemma Nutrition research (New York, N.Y.) Aging leads to a number of physiological alterations, specifically changes in circulating hormone levels, increases in fat deposition, decreases in metabolism, changes in inflammatory responses, and reductions in growth factors. These progressive changes in physiology and metabolism are exacerbated by modern culture and Western diet and give rise to diseases such as obesity, metabolic syndrome, and type 2 (non-insulin-dependent) diabetes (T2D). These age and lifestyle-related metabolic diseases are often accompanied by insulin and leptin resistance, as well as aberrant amylin production and signaling. Many of these alterations in hormone production and signaling are directly influenced by an increase in both oxidative stress and inflammation. Importantly, changes in hormone production and signaling have direct effects on brain function and the development of age-related neurologic disorders. Therefore, this review aims to present evidence on the effects that diet and metabolic disease have on age-related cognitive decline and the development of cognitive diseases, particularly Alzheimer disease. This review will focus on the metabolic hormones insulin, leptin, and amylin and their role in cognitive decline, as well as the therapeutic potential of these hormones in treating cognitive disease. Future investigations targeting the long-term effects of insulin and leptin treatment may reveal evidence to reduce risk of cognitive decline and Alzheimer disease. 10.1016/j.nutres.2016.11.002
    Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study. Romo Matthew L,Schooling C Mary Neuroendocrinology BACKGROUND:Observational evidence regarding the role of leptin in Alzheimer disease (AD) is conflicting. We sought to determine the causal role of circulating leptin and soluble plasma leptin receptor (sOB-R) levels in AD using a separate-sample Mendelian randomization study. METHODS:Single nucleotide polymorphisms (SNPs) independently and solely predictive of log-transformed leptin (rs10487505 [LEP], rs780093 [GCKR], rs900400 [CCNL1], rs6071166 [SLC32A1], and rs6738627 [COBLL1]) and of sOB-R (rs1137101 [LEPR], rs2767485 [LEPR], and rs1751492 [LEPR]) levels (ng/mL) were obtained from 2 previously reported genome-wide association studies. We obtained associations of leptin and sOB-R levels with AD using inverse variance weighting with fixed effects by combining Wald estimates for each SNP. Sensitivity analyses included using weighted median and MR-Egger methods and repeating the analyses using only SNPs of genome-wide significance. RESULTS:Using inverse variance weighting, genetically predicted circulating leptin levels were not associated with AD, albeit with wide confidence intervals (CIs): odds ratio (OR) 0.99 per log-transformed ng/mL; 95% CI 0.55-1.78. Similarly, the association of sOB-R with AD was null using inverse variance weighting (OR 1.08 per log-transformed ng/mL; 95% CI 0.83-1.41). Results from our sensitivity analyses confirmed our findings. CONCLUSIONS:In this first Mendelian randomization study estimating the causal effect of leptin on AD, we did not find an effect of genetically predicted circulating leptin and sOB-R levels on AD. As such, this study suggests that leptin is unlikely to be a major contributor to AD, although the wide CIs preclude a definitive assessment. 10.1159/000475713
    Low Plasma Leptin and High Soluble Leptin Receptor Levels Are Associated With Mild Cognitive Impairment in Type 2 Diabetic Patients. Yin Han,Tian Sai,Huang Rong,Cai Rongrong,Guo Dan,Lin Hongyan,Wang Jiaqi,Wang Shaohua Frontiers in aging neuroscience Metabolic disturbances, such as hyperglycemia, hyperlipidemia, and obesity, are thought to be risk factors for Alzheimer's disease. This study aimed to investigate whether adipokine leptin and soluble leptin receptor (sOBR) levels are correlated with mild cognitive impairment (MCI) and metabolic status of the patients of type 2 diabetes mellitus (T2DM). Total of 169 T2DM patients were recruited and divided according to the Montreal Cognitive Assessment (MoCA) score. Their cognition and metabolic parameters were extensively assessed. Plasma leptin and sOBR levels were determined by RIA and ELISA, respectively. Free leptin index (FLI) was calculated. Of 124 enrolled T2DM patients, 61 were diagnosed with MCI (MoCA < 26). In MCI group and female subgroup, leptin levels and FLI were significantly lower and sOBR concentrations were higher when compared with their respective health cognition controls (all < 0.05). Leptin levels and FLI were positively associated with the most cognitive domains and their Waist-to-Hip Ratio (WHR), a traditional index of central obesity. Leptin, sOBR, and WHR were independent variables of MCI in all individuals (all < 0.05). For the females, MoCA was also positively correlated with leptin (β = 0.893, < 0.001) and negatively correlated with WHR (β = -0.363, = 0.014). Leptin was positively correlated only with WHR (β = 0.441, = 0.025). This study showed that a high level of leptin and low level of sOBR are associated with the improved cognitive function in T2DM patients and more significantly in female individuals, while WHR, as an indicator of the visceral obesity, contributes to cognitive deficits. Advanced Glycation End Products Induced Cognitive Impairment in Diabetes: BDNF Signal Meditated Hippocampal Neurogenesis ChiCTR-OCC-15006060; http://www.chictr.org.cn/showproj.aspx?proj=10536. 10.3389/fnagi.2018.00132
    Role of Leptin in Mood Disorder and Neurodegenerative Disease. Zou Xiaohan,Zhong Lili,Zhu Cuilin,Zhao Haisheng,Zhao Fangyi,Cui Ranji,Gao Shuohui,Li Bingjin Frontiers in neuroscience The critical regulatory role of leptin in the neuroendocrine system has been widely reported. Significantly, leptin can improve learning and memory, affect hippocampal synaptic plasticity, exert neuroprotective efficacy and reduce the risk of several neuropsychiatric diseases. In terms of depression, leptin could modulate the levels of neurotransmitters, neurotrophic factors and reverse the dysfunction in the hypothalamic-pituitary-adrenal axis (HPA). At the same time, leptin affects neurological diseases during the regulation of metabolic homeostasis. With regards to neurodegenerative diseases, leptin can affect them via neuroprotection, mainly including Alzheimer's disease and Parkinson's disease. This review will summarize the mechanisms of leptin signaling within the neuroendocrine system with respect to these diseases and discuss the therapeutic potential of leptin. 10.3389/fnins.2019.00378
    Regulation of Hippocampal Synaptic Function by the Metabolic Hormone, Leptin: Implications for Health and Neurodegenerative Disease. McGregor Gemma,Harvey Jenni Frontiers in cellular neuroscience The role of the endocrine hormone leptin in controlling energy homeostasis in the hypothalamus are well documented. However the CNS targets for leptin are not restricted to the hypothalamus as a high density of leptin receptors are also expressed in several parts of the brain involved in higher cognitive functions including the hippocampus. Numerous studies have identified that in the hippocampus, leptin has cognitive enhancing actions as exogenous application of this hormone facilitates hippocampal-dependent learning and memory, whereas lack or insensitivity to leptin results in significant memory deficits. Leptin also markedly influences some of the main cellular changes that are involved in learning and memory including NMDA-receptor dependent synaptic plasticity and glutamate receptor trafficking. Like other metabolic hormones, there is a significant decline in neuronal sensitivity to leptin during the ageing process. Indeed, the capacity of leptin to modulate the functioning of hippocampal synapses is substantially reduced in aged compared to adult tissue. Clinical studies have also identified an association between circulating leptin levels and the risk of certain neurodegenerative disorders such as Alzheimer's disease (AD). In view of this, targeting leptin and/or its receptor/signaling mechanisms may be an innovative approach for developing therapies to treat AD. In support of this, accumulating evidence indicates that leptin has cognitive enhancing and neuroprotective actions in various models of AD. Here we assess recent evidence that supports an important regulatory role for leptin at hippocampal CA1 synapses, and we discuss how age-related alterations in this hormonal system influences neurodegenerative disease. 10.3389/fncel.2018.00340
    Central Regulation of Glucose Homeostasis. Tups Alexander,Benzler Jonas,Sergi Domenico,Ladyman Sharon R,Williams Lynda M Comprehensive Physiology The ability of the brain to directly control glucose levels in the blood independently of its effects on food intake and body weight has been known ever since 1854 when Claude Bernard, a French physiologist, discovered that lesioning the floor of the fourth ventricle in rabbits led to a rise of sugar in the blood. Despite this outstanding discovery at that time, it took more than 140 years before progress started to be made in identifying the underlying mechanisms of brain-mediated control of glucose homeostasis. Technological advances including the generation of brain insulin receptor null mice revealed that insulin action specifically in the central nervous system is required for the regulation of glucose metabolism, particularly in the modulation of hepatic glucose production. Furthermore, it was established that the hormone leptin, known for its role in regulating food intake and body weight, actually exerts its most potent effects on glucose metabolism, and that this function of leptin is mediated centrally. Under certain circumstances, high levels of leptin can replicate the actions of insulin, thus challenging the idea that life without insulin is impossible. Disruptions of central insulin signaling and glucose metabolism not only lead to impairments in whole body glucose homeostasis, they also have other serious consequences, including the development of Alzheimer's disease which is sometimes referred to as type 3 diabetes reflecting its common etiology with type 2 diabetes. © 2017 American Physiological Society. Compr Physiol 7:471-764, 2017. 10.1002/cphy.c160015
    Obesity, diabetes, and leptin resistance promote tau pathology in a mouse model of disease. Platt T L,Beckett T L,Kohler K,Niedowicz D M,Murphy M P Neuroscience Obesity and type 2 diabetes mellitus (T2DM) convey an increased risk for developing dementia. The microtubule-associated protein tau is implicated in neurodegenerative disease by undergoing hyperphosphorylation and aggregation, leading to cytotoxicity and neurodegeneration. Enzymes involved in the regulation of tau phosphorylation, such as GSK3β, are tightly associated with pathways found to be dysregulated in T2DM. We have shown previously that leptin-resistant mice, which develop obesity and a diabetic phenotype, display elevated levels of tau phosphorylation. Here we show cells cultured with leptin, an adipokine shown to have neuroprotective effects, reduces tau phosphorylation. To explore how this mechanism works in vivo we transduced an existing diabetic mouse line (Lepr(db/db)) with a tau mutant (tau(P301L)) via adeno-associated virus (AAV). The resulting phenotype included a striking increase in tau phosphorylation and the number of neurofibrillary tangles (NFTs) found within the hippocampus. We conclude that leptin resistance-induced obesity and diabetes accelerates the development of tau pathology. This model of metabolic dysfunction and tauopathy provides a new system in which to explore the mechanisms underlying the ways in which leptin resistance and diabetes influence development of tau pathology, and may ultimately be related to the development of NFTs. 10.1016/j.neuroscience.2015.12.011
    The Role of the Adipocyte Hormone Leptin in Alzheimer's Disease. Ishii Makoto The Keio journal of medicine Cognitive deficits are the major manifestation of Alzheimer's disease (AD); however, weight loss can precede the mental decline and correlates with disease severity. Thus, brain circuits controlling body weight may be altered early in AD and could be intrinsic to AD pathobiology. In mouse models, we found that amyloid-beta, a major pathogenic factor in AD, could inhibit hypothalamic neurons in the leptin pathway, which was associated with early body weight/metabolic deficits. Ongoing research seeks to elucidate the mechanisms underlying the body weight/metabolic deficits and hypothalamic dysfunction in AD using both mouse models and clinically relevant human studies.(Presented at the 1919th Meeting, March 2, 2016). 10.2302/kjm.65-002-ABST
    Age-dependent regulation of excitatory synaptic transmission at hippocampal temporoammonic-CA1 synapses by leptin. McGregor Gemma,Clements Leigh,Farah Adham,Irving Andrew J,Harvey Jenni Neurobiology of aging The hippocampus is a key target for the hormone leptin and leptin regulation of excitatory synaptic transmission at Schaffer-collateral-CA1 synapses during aging are well documented. However, little is known about the age-dependent actions of leptin at the temporoammonic (TA) input to CA1 neurons. Here we show that leptin induces a novel form of N-methyl-D-aspartate receptor-dependent long-term depression (LTD) at adult (12-24 weeks old) TA-CA1 synapses. Leptin-induced LTD requires activation of canonical Janus tyrosine kinase 2- signal transducer and activator of transcription signaling and removal of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors from synapses. Moreover, leptin-induced LTD is occluded by activity-dependent LTD at TA-CA1 synapses. By contrast, leptin has no effect on excitatory synaptic transmission at aged (12-14 months old) TA-CA1 synapses, and low-frequency stimulation also fails to induce LTD at this age. These findings demonstrate clear age-related alterations in the leptin sensitivity of TA-CA1 synapses and provide valuable information on how the leptin system alters with age. As leptin has been linked to Alzheimer's disease, these findings have important implications for understanding of age-related disorders such as Alzheimer's disease. 10.1016/j.neurobiolaging.2018.05.007
    Adiponectin Receptors Are Less Sensitive to Stress in a Transgenic Mouse Model of Alzheimer's Disease. Várhelyi Zoltán P,Kálmán János,Oláh Zita,Ivitz Eszter V,Fodor Eszter K,Sántha Miklós,Datki Zsolt L,Pákáski Magdolna Frontiers in neuroscience Adiponectin and leptin are implicated in the initiation and pathomechanism of Alzheimer's disease (AD). The serum concentrations of these adipokines has been extensively studied in AD, however little is known about their receptors in this disease. We developed a novel approach to examine whether the receptors of adiponectin (AdipoR1 and -R2) and/or leptin (LepR) can contribute to AD pathomechanism. To achieve this, we investigated the effect of both genetic and environmental factors associated with AD on the expression of these receptors. We used C57BL/6J (WT) and APP(swe)/Presen(e9d)1 (AD) mice. Both strains were exposed to restraint stress (RS) daily for 6h over different time periods. Then, we measured the mRNA expression of AdipoR1, AdipoR2 and LepR and the level of AdipoR1 and AdipoR2 proteins in the hippocampal and prefrontal cortical areas of each mouse. We detected brain region specific transcriptomic changes of adiponectin receptors induced by APP and PS1 transgenes. Both acute and chronic RS caused significant elevations in AdipoR1 mRNA expression in the hippocampus of WT mice. In the prefrontal cortex, the mRNA expression of AdipoR1 followed a biphasic course. In AD mice, RS did not promote any changes in the expression of AdipoR1 mRNA and AdipoR1 protein levels. AdipoR2 mRNA in AD animals, however, showed a significant increase in the prefrontal cortex during RS. Regarding AdipoR1 and AdipoR2 mRNA and protein expression, relevant changes could be measured during stress exposure in both brain areas. Furthermore, stress exposed groups exhibited little change in LepR mRNA expression. Our findings indicate that carrying the transgenes associated with AD induces modification in the expression of both adiponectin receptors. In the case of a normal genetic background, these receptors also appear to be sensitive to environmental factors, while in a genetically determined AD model less response to stress stimuli could be observed. The results suggest that modification of adipokine receptors could also be considered in the therapeutic approach to AD. 10.3389/fnins.2017.00199
    Obesity as a Risk Factor for Alzheimer's Disease: Implication of Leptin and Glutamate. Lloret Ana,Monllor Paloma,Esteve Daniel,Cervera-Ferri Ana,Lloret Maria-Angeles Frontiers in neuroscience Obesity is known to induce leptin and insulin resistance. Leptin is a peptide hormone synthesized in adipose tissue that mainly regulates food intake. It has been shown that insulin stimulates the production of leptin when adipocytes are exposed to glucose to encourage satiety; while leptin, via a negative feedback, decreases the insulin release and enhances tissue sensitivity to it, leading to glucose uptake for energy utilization or storage. Therefore, resistance to insulin is closely related to leptin resistance. Obesity in middle age has also been related to Alzheimer's disease (AD). In recent years, the relation between impaired leptin signaling pathway and the onset of AD has been studied. In all this context the role of the blood brain barrier (BBB) is crucial. Slow excitotoxicity happens in AD due to an excess of the neurotransmitter glutamate. Since leptin has been shown to regulate -methyl-D-aspartate (NMDA) receptors, we want to review the link between these pathological pathways, and how they are affected by other AD triggering factors and its role in the onset of AD. 10.3389/fnins.2019.00508
    The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer's Disease. Forny-Germano Leticia,De Felice Fernanda G,Vieira Marcelo Nunes do Nascimento Frontiers in neuroscience Cross-talk between adipose tissue and central nervous system (CNS) underlies the increased risk of obese people to develop brain diseases such as cognitive and mood disorders. Detailed mechanisms for how peripheral changes caused by adipose tissue accumulation in obesity impact the CNS to cause brain dysfunction are poorly understood. Adipokines are a large group of substances secreted by the white adipose tissue to regulate a wide range of homeostatic processes including, but not limited to, energy metabolism and immunity. Obesity is characterized by a generalized change in the levels of circulating adipokines due to abnormal accumulation and dysfunction of adipose tissue. Altered adipokine levels underlie complications of obesity as well as the increased risk for the development of obesity-related comorbidities such as type 2 diabetes, cardiovascular and neurodegenerative diseases. Here, we review the literature for the role of adipokines as key mediators of the communication between periphery and CNS in health and disease. We will focus on the actions of leptin and adiponectin, two of the most abundant and well studied adipokines, in the brain, with particular emphasis on how altered signaling of these adipokines in obesity may lead to cognitive dysfunction and augmented risk for Alzheimer's disease. A better understanding of adipokine biology in brain disorders may prove of major relevance to diagnostic, prevention and therapy. 10.3389/fnins.2018.01027
    A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions of Leptin. Malekizadeh Yasaman,Holiday Alison,Redfearn Devon,Ainge James A,Doherty Gayle,Harvey Jenni Cerebral cortex (New York, N.Y. : 1991) A key pathology of Alzheimer's disease (AD) is amyloid β (Aβ) accumulation that triggers synaptic impairments and neuronal death. Metabolic disruption is common in AD and recent evidence implicates impaired leptin function in AD. Thus the leptin system may be a novel therapeutic target in AD. Indeed, leptin has cognitive enhancing properties and it prevents the aberrant effects of Aβ on hippocampal synaptic function and neuronal viability. However, as leptin is a large peptide, development of smaller leptin-mimetics may be the best therapeutic approach. Thus, we have examined the cognitive enhancing and neuroprotective properties of known bioactive leptin fragments. Here we show that the leptin (116-130) fragment, but not leptin (22-56), mirrored the ability of leptin to promote AMPA receptor trafficking to synapses and facilitate activity-dependent hippocampal synaptic plasticity. Administration of leptin (116-130) also mirrored the cognitive enhancing effects of leptin as it enhanced performance in episodic-like memory tests. Moreover, leptin (116-130) prevented hippocampal synaptic disruption and neuronal cell death in models of amyloid toxicity. These findings establish further the importance of the leptin system as a therapeutic target in AD. 10.1093/cercor/bhw272
    Leptin, hsCRP, TNF-α and IL-6 levels from normal aging to dementia: Relationship with cognitive and functional status. Magalhães Carolina A,Ferreira Cláudia N,Loures Cristina M G,Fraga Vanessa G,Chaves Amanda C,Oliveira Ana Carolina R,de Souza Leonardo C,Resende Elisa de P F,Carmona Karoline C,Guimarães Henrique C,Cintra Marco T G,Lanna Igor N,Zauli Danielle A G,Bicalho Maria A,Carvalho Maria G,Sousa Lirlândia P,Caramelli Paulo,Gomes Karina B Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Cognitive impairment, including mild cognitive impairment (MCI) and dementia, compromises the patients' cognitive abilities and, to different extents, to carry out daily activities, accompanied by personality and behavioral changes. Studies suggest that leptin, an adipokine, has a neuroprotective role against Alzheimer's disease (AD) and that cytokines are associated with inflammatory processes and dementia. This study aimed to evaluate serum leptin, hsCRP, IL-6 and TNF-α levels in a cognitive continuum group from normal to demential status, and to assess whether they correlates to Mini-Mental State Examination (MMSE) and Functional Assessment Staging (FAST) scores. Forty-three participants were included, of whom 12 with probable AD, 18 with MCI and 13 with no objective cognitive decline. Serum leptin and hsCRP levels were evaluated by immunoturbidimetric method, and IL-6 and TNF-α by ELISA. Higher TNF-α levels were found in individuals with FAST stages 1/2 and normal scores evaluated by MMSE. hsCRP levels were inversely correlated with FAST stages. No association with function or global cognition was observed for leptin and IL-6 levels. However, women presented higher leptin serum levels than men while lower leptin and IL-6 levels were observed in individuals aged ≥59 years. Our results suggest that TNF-α is associated with cognitive and functional decline and that inflammation could be a substrate of cognitive impairment at early clinical stages of dementia. 10.1016/j.jocn.2018.08.027
    Association between Adipokines and Biomarkers of Alzheimer's Disease: A Cross-Sectional Study. Letra Liliana,Matafome Paulo,Rodrigues Tiago,Duro Diana,Lemos Raquel,Baldeiras Inês,Patrício Miguel,Castelo-Branco Miguel,Caetano Gina,Seiça Raquel,Santana Isabel Journal of Alzheimer's disease : JAD BACKGROUND:Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer's disease. However, the involvement of adipokines, particularly adiponectin, remains unclear. OBJECTIVE:To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer's disease and evaluate their relationship with classical biomarkers and their value as markers of progression. METHODS:Amnestic mild cognitive impairment (MCI, n = 71) and Alzheimer's dementia (AD, n = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman's correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines. RESULTS:Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μg/ml maximized the sum of specificity (87%) and sensitivity (44%). CONCLUSION:Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer's disease. 10.3233/JAD-180669
    Leptin Dysfunction and Alzheimer's Disease: Evidence from Cellular, Animal, and Human Studies. McGuire Matthew J,Ishii Makoto Cellular and molecular neurobiology There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer's disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools. 10.1007/s10571-015-0282-7
    Effects of Gender and Other Confounding Factors on Leptin Concentrations in Alzheimer's Disease: Evidence from the Combined Analysis of 27 Case-Control Studies. Zhou Futao,Chen Shuangrong Journal of Alzheimer's disease : JAD Leptin, as a link between fat mass and the brain, has been reported to be associated with gender. The gender differences in leptin levels between Alzheimer's disease (AD) and healthy elderly controls are inconclusive so far. To quantitatively summarize the leptin data available from female and male patients with AD, we searched PubMed and EMBASE for articles published from inception to July 20, 2017. Data were extracted from 27 studies, consisting of 3,014 participants. The pooled results showed that the overall leptin levels were lower in AD (Hedges' g = -0.481; p = 0.002) than in controls, and the leptin levels in whole blood and serum were decreased with moderate and large effect sizes (g = -0.677, -0.839; respectively; both of p-values <0.001) in AD compared with controls. In blood, there were significantly lower concentrations of leptin in female AD than in female controls (g = -0.590; p = 0.014), but not in male case-control group (g = -0.666; p = 0.067). Meta-regression analysis demonstrated that the decreased extent of leptin levels in AD paralleled the degree of the severity of dementia symptoms, as well as the alterations of body mass index (p-values ≤0.002). The findings provide strong evidence that 1) the blood concentrations of leptin are lower in female AD patients than in female controls; and 2) the greater the severity of dementia symptoms, the greater the decreases in the blood leptin levels. But more future investigations on the blood leptin levels in male AD patients is warranted. 10.3233/JAD-170983
    Disruption of leptin signalling in a mouse model of Alzheimer's disease. King Anna,Brain Anna,Hanson Kelsey,Dittmann Justin,Vickers James,Fernandez-Martos Carmen Metabolic brain disease Disruption of leptin signalling has been implicated as playing a role in the development of Alzheimer's disease (AD). Leptin has previously been shown to be affected by amyloid-beta (Aβ)-related signalling; however, pathways that link leptin to the disease pathogenesis have not been determined. To characterize the association between increasing age-dependent Aβ levels with leptin signalling and the vulnerable brain regions in AD, we assessed the mRNA and protein expression profile of leptin and leptin receptor (Ob-Rb) at 9 and 18-month-age in APP/PS1 mice. Immunohistochemical labelling demonstrated that leptin and Ob-Rb proteins were localised to neocortical and hippocampal neurons in APP/PS1 and wildtype (WT) mice. Neuronal leptin and Ob-Rb immunolabelling was more prominent in the neocortex of both groups at 9 month of age, while, at 18 months, labelling was reduced in the hippocampus of APP/PS1 mice relative to WT. Immunoblotting analysis demonstrated decreased hippocampal leptin levels, concomitantly with an increased Ob-Rb levels, in APP/PS1 mice compared with WT controls at 18 month of age. While no leptin mRNA was found in either of the groups analysed, Ob-Rb mRNA was significantly decreased in the hippocampus of APP/PS1 mice at both ages analysed. In addition, a significant decreased protein kinase B (Akt) activity concomitantly with an upregulation of suppressor of cytokine signaling-3 (SOCS3) and protein-tyrosine phosphatase 1B (PTP1B) transcripts was present. Thus, these results collectively indicate alterations of leptin signalling in the hippocampus of APP/PS1 mice, providing novel insights about the pathways that could link aberrant leptin signaling to the pathological changes of AD. 10.1007/s11011-018-0203-9
    Food for thought: Leptin regulation of hippocampal function and its role in Alzheimer's disease. McGregor Gemma,Harvey Jenni Neuropharmacology Accumulating evidence indicates that diet and body weight are important factors associated with Alzheimer's disease (AD), with a significant increase in AD risk linked to mid-life obesity, and weight loss frequently occurring in the early stages of AD. This has fuelled interest in the hormone leptin, as it is an important hypothalamic regulator of food intake and body weight, but leptin also markedly influences the functioning of the hippocampus; a key brain region that degenerates in AD. Increasing evidence indicates that leptin has cognitive enhancing properties as it facilitates the cellular events that underlie hippocampal-dependent learning and memory. However, significant reductions in leptin's capacity to regulate hippocampal synaptic function occurs with age and dysfunctions in the leptin system are associated with an increased risk of AD. Moreover, leptin is a potential novel target in AD as leptin treatment has beneficial effects in various models of AD. Here we summarise recent advances in leptin neurobiology with particular focus on regulation of hippocampal synaptic function by leptin and the implications of this for neurodegenerative disorders like AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' 10.1016/j.neuropharm.2017.09.038
    A high-sucrose diet aggravates Alzheimer's disease pathology, attenuates hypothalamic leptin signaling, and impairs food-anticipatory activity in APPswe/PS1dE9 mice. Yeh Skye Hsin-Hsien,Shie Feng-Shiun,Liu Hui-Kang,Yao Heng-Hsiang,Kao Pei-Chen,Lee Yi-Heng,Chen Li-Min,Hsu Shu-Meng,Chao Li-Jung,Wu Kuan-Wei,Shiao Young-Ji,Tsay Huey-Jen Neurobiology of aging High-fat and high-sugar diets contribute to the prevalence of type 2 diabetes and Alzheimer's disease (AD). Although the impact of high-fat diets on AD pathogenesis has been established, the effect of high-sucrose diets (HSDs) on AD pathogenesis remains unclear. This study sought to determine the impact of HSDs on AD-related pathologies. Male APPswe/PS1dE9 (APP/PS1) transgenic and wild-type mice were provided with HSD and their cognitive and hypothalamus-related noncognitive parameters, including feeding behaviors and glycemic regulation, were compared. HSD-fed APP/PS1 mice showed increased neuroinflammation, as well as increased cortical and serum levels of amyloid-β. HSD-fed APP/PS1 mice showed aggravated obesity, hyperinsulinemia, insulin resistance, and leptin resistance, but there was no induction of hyperphagia or hyperleptinemia. Leptin-induced phosphorylation of signal transducer and activator of transcription 3 in the dorsomedial and ventromedial hypothalamus was reduced in HSD-fed APP/PS1 mice, which might be associated with attenuated food-anticipatory activity, glycemic dysregulation, and AD-related noncognitive symptoms. Our study demonstrates that HSD aggravates metabolic stresses, increases AD-related pathologies, and attenuates hypothalamic leptin signaling in APP/PS1 mice. 10.1016/j.neurobiolaging.2019.11.018
    Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory. Yook Jang Soo,Rakwal Randeep,Shibato Junko,Takahashi Kanako,Koizumi Hikaru,Shima Takeru,Ikemoto Mitsushi J,Oharomari Leandro K,McEwen Bruce S,Soya Hideaki Proceedings of the National Academy of Sciences of the United States of America Regular exercise and dietary supplements with antioxidants each have the potential to improve cognitive function and attenuate cognitive decline, and, in some cases, they enhance each other. Our current results reveal that low-intensity exercise (mild exercise, ME) and the natural antioxidant carotenoid astaxanthin (AX) each have equivalent beneficial effects on hippocampal neurogenesis and memory function. We found that the enhancement by ME combined with AX in potentiating hippocampus-based plasticity and cognition is mediated by leptin (LEP) made and acting in the hippocampus. In assessing the combined effects upon wild-type (WT) mice undergoing ME with or without an AX diet for four weeks, we found that, when administrated alone, ME and AX separately enhanced neurogenesis and spatial memory, and when combined they were at least additive in their effects. DNA microarray and bioinformatics analyses revealed not only the up-regulation of an antioxidant gene, , but also that the up-regulation of gene expression in the hippocampus of WT mice with ME alone is further enhanced by AX. Together, they also increased hippocampal LEP (h-LEP) protein levels and enhanced spatial memory mediated through AKT/STAT3 signaling. AX treatment also has direct action on human neuroblastoma cell lines to increase cell viability associated with increased LEP expression. In LEP-deficient mice (), chronic infusion of LEP into the lateral ventricles restored the synergy. Collectively, our findings suggest that not only h-LEP but also exogenous LEP mediates effects of ME on neural functions underlying memory, which is further enhanced by the antioxidant AX. 10.1073/pnas.1815197116