LW-AFC, A New Formula Derived from Liuwei Dihuang Decoction, Ameliorates Cognitive Deterioration and Modulates Neuroendocrine-Immune System in SAMP8 Mouse.
Wang Jianhui,Zhang Xiaorui,Cheng Xiaorui,Cheng Junping,Liu Feng,Xu Yiran,Zeng Ju,Qiao Shanyi,Zhou Wenxia,Zhang Yongxiang
Current Alzheimer research
BACKGROUND:Alzheimer's disease (AD), the most common cause of dementia among older people, could not be prevented, halted, or reversed up till now. A large body of pharmacological study has revealed that Liuwei Dihuang decoction (LW), a classical traditional Chinese medicinal prescription, possesses potential therapeutic effects on AD. LW-AFC is key fractions from LW. METHOD:Cognition ability was evaluated by behavioral experiments. Using multiplex bead analysis, radioimmunoassay, immunochemiluminometry and ELISA to determine levels of cytokines and hormones. The splenocyte proliferation and peripheral lymphocyte subsets was investigated by 3H-thymidine incorporation and flow cytometric analysis, respectively. RESULTS:This study showed the treatment of LW-AFC slowed the aging process of senescence-accelerated mouse prone 8 strain (SAMP8), a robust model sporadic AD or late-onset/age-related AD. LW-AFC had ameliorative effects on spontaneous locomotor activity, object recognition memory, spatial learning and memory, passive and active avoidance impairment in SAMP8 mice. Administration of LW-AFC restored the imbalance of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axis, enhanced the proliferation of splenocytes, corrected the disorder of lymphocyte subsets, and regulated the abnormal production of cytokine in SAMP8 mice. Effects of LW-AFC on pharmacodynamics and neuroendocrine immunomodulation network in SAMP8 mice were better than memantine and donepezil. CONCLUSION:This data indicated LW-AFC may be a promising therapeutic medicine for AD.
10.2174/1567205013666160603001637
A combination of indomethacin and atorvastatin ameliorates cognitive and pathological deterioration in PrP-hAβPPswe/PS1 transgenic mice.
Wang Jianhui,Cheng Xiaorui,Zhang Xiaorui,Liu Gang,Wang Yongan,Zhou Wenxia,Zhang Yongxiang
Journal of neuroimmunology
Mounting evidence has shown that inflammation might drive Alzheimer's disease (AD) pathology and contribute to its exacerbation. Previous studies have indicated that indomethacin or atorvastatin are beneficial in treating AD; however, no significant clinical effects have been shown. Furthermore, no study has investigated the efficacy of combining these agents for treating AD. This study sought to determine the effect of a combination of indomethacin and atorvastatin in the PrP-hAβPPswe/PS1 (APP/PS1) transgenic AD mouse model. Treatment with indomethacin and atorvastatin ameliorated impairments in spatial learning and memory, and the active avoidance response in APP/PS1 mice. Moreover, we found a suppression of Aβ plaques and decreased concentration of Aβ in the hippocampus of APP/PS1 mice following treatment. In addition, indomethacin and atorvastatin ameliorated abnormal cytokine secretion, lymphocyte subset disorder, and hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axis imbalances in APP/PS1 mice. The combination of indomethacin and atorvastatin restored immune and neuroendocrine processes, attenuated pathologic changes and cognitive impairments in APP/PS1 transgenic mice, and could thus be a potential therapeutic agent for AD.
10.1016/j.jneuroim.2019.03.003
The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.
Batalha Vânia L,Ferreira Diana G,Coelho Joana E,Valadas Jorge S,Gomes Rui,Temido-Ferreira Mariana,Shmidt Tatiana,Baqi Younis,Buée Luc,Müller Christa E,Hamdane Malika,Outeiro Tiago F,Bader Michael,Meijsing Sebastiaan H,Sadri-Vakili Ghazaleh,Blum David,Lopes Luísa V
Scientific reports
Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer's and age-related cognitive impairments may rely on its ability to modulate GR actions.
10.1038/srep31493
New selective glucocorticoid receptor modulators reverse amyloid-β peptide-induced hippocampus toxicity.
Pineau Fanny,Canet Geoffrey,Desrumaux Catherine,Hunt Hazel,Chevallier Nathalie,Ollivier Matthias,Belanoff Joseph K,Givalois Laurent
Neurobiology of aging
In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuroinflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-β peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment.
10.1016/j.neurobiolaging.2016.05.018
Phosphodiesterase-2 Inhibitor Bay 60-7550 Ameliorates Aβ-Induced Cognitive and Memory Impairment via Regulation of the HPA Axis.
Ruan Lina,Du Kai,Tao Mengjia,Shan Chunyan,Ye Ruixuan,Tang Yali,Pan Hanbo,Lv Jinpeng,Zhang Meixi,Pan Jianchun
Frontiers in cellular neuroscience
The dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is often seen in Alzheimer's disease (AD) patients with cognitive deficits. Selective inhibition of phosphodiesterase (PDE) 4 and 5 has already proven to be effective in reducing beta-amyloid 1-42 (Aβ1-42)-mediated pathology by regulating corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, suggesting that PDE-dependent signaling is involved in Aβ1-42-induced HPA axis dysfunction. However, nausea and vomiting are the side effects of some PDE4 inhibitors, which turn our attention to other PDEs. PDE2 are highly expressed in the hippocampus and cortex, which associate with learning and memory, but not in the area postrema that would cause vomiting. The present study suggested that microinjection of Aβ1-42 to the intracerebroventricle induced learning and memory impairments and dysregulation of the HPA axis by increased expression of CRF and GR. However, the PDE2 inhibitor Bay 60-7550 significantly ameliorated the learning and memory impairment in the Morris water maze (MWM) and step-down passive avoidance tests. The Aβ1-42-induced increased CRF and GR levels were also reversed by the treatment with Bay 60-7550. These Bay 60-7550's effects were prevented by pretreatment with the PKG inhibitor KT5823. Moreover, the Bay 60-7550-induced downstream phosphorylation of cyclic AMP response element binding (pCREB) and brain-derived neurotrophic factor (BDNF) expression was also prevented (or partially prevented) by KT5823 or the PKA inhibitor H89. These results may lead to the discovery of novel strategies for the treatment of age-related cognitive disorders, such as AD, which affects approximately 44 million people worldwide.
10.3389/fncel.2019.00432
Environmental novelty exacerbates stress hormones and Aβ pathology in an Alzheimer's model.
Stuart Kimberley E,King Anna E,Fernandez-Martos Carmen M,Summers Mathew J,Vickers James C
Scientific reports
Cognitive stimulation has been proposed as a non-pharmacological intervention to be used in primary, secondary and tertiary prevention approaches for Alzheimer's disease. A common familial Alzheimer's disease transgenic model showed heightened levels of the stress hormone, corticosterone. When exposed to periodic enhanced cognitive stimulation, these animals demonstrated further heightened levels of corticosterone as well as increased Aβ pathology. Hence, Alzheimer's disease may be associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, causing stimulatory environments to become stress-inducing, leading to a glucocorticoid-pathology cycle contributing to further Aβ release and plaque formation. This finding suggests that stimulation-based interventions and local environments for people with Alzheimer's disease need to be designed to minimise a stress response that may exacerbate brain pathology.
10.1038/s41598-017-03016-0
Central Role of Glucocorticoid Receptors in Alzheimer's Disease and Depression.
Canet Geoffrey,Chevallier Nathalie,Zussy Charleine,Desrumaux Catherine,Givalois Laurent
Frontiers in neuroscience
Alzheimer's disease (AD) is the principal neurodegenerative pathology in the world displaying negative impacts on both the health and social ability of patients and inducing considerable economic costs. In the case of sporadic forms of AD (more than 95% of patients), even if mechanisms are unknown, some risk factors were identified. The principal risk is aging, but there is growing evidence that lifetime events like chronic stress or stress-related disorders may increase the probability to develop AD. This mini-review reinforces the rationale to consider major depressive disorder (MDD) as an important risk factor to develop AD and points the central role played by the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids (GC) and their receptors (GR) in the etiology of MDD and AD. Several strategies directly targeting GR were tested to neutralize the HPA axis dysregulation and GC overproduction. Given the ubiquitous expression of GR, antagonists have many undesired side effects, limiting their therapeutic potential. However, a new class of molecules was developed, highly selective and acting as modulators. They present the advantage to selectively abrogate pathogenic GR-dependent processes, while retaining beneficial aspects of GR signaling. In fact, these "selective GR modulators" induce a receptor conformation that allows activation of only a subset of downstream signaling pathways, explaining their capacity to combine agonistic and antagonistic properties. Thus, targeting GR with selective modulators, alone or in association with current strategies, becomes particularly attractive and relevant to develop novel preventive and/or therapeutic strategies to tackle disorders associated with a dysregulation of the HPA axis.
10.3389/fnins.2018.00739
Inhibition of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment by Regulation of HPA Axis Related cAMP Signaling.
Xu Ying,Zhu Naping,Xu Wen,Ye Han,Liu Kaiping,Wu Feiyan,Zhang Meixi,Ding Yun,Zhang Chong,Zhang Hanting,O'Donnell James,Pan Jiangchun
Frontiers in aging neuroscience
Beta amyloid peptides (Aβ) are found to be associated with dysfunction of hypothalamic-pituitary-adrenal axis (HPA axis) that leads to memory and cognitive deficits in patients with Alzheimer's disease (AD). Phosphodiesterase 4 (PDE4) inhibitors increase the intracellular cAMP activities, which may ameliorate cognitive deficits associated with AD. However, it remains unclear whether PDE4-mediated reversal of cognitive impairment in mouse model of AD is related to HPA axis and downstream cAMP-dependent pathway. The present study investigated the effects of PDE4 inhibitor rolipram on Aβ1-42-induced cognitive dysfunction and its underlying mechanisms. The step-down passive avoidance (PA) and Morris water-maze (MWM) tests were conducted 1 week (1 W), 2 months (2 M), and 6 months (6 M) after intracerebroventricular microjection (i.c.v.) of Aβ1-42. The results suggested that memory impairment emerged as early as 1 W, peaked at 2 M, and lasted until 6 M after injection. Chronic treatment with rolipram (0.1, 0.5, 1.0 mg/kg/d, i.p.) for 2 weeks (i.e., treatment started at 1.5 months after Aβ1-42 microinjection) dose-dependently improved memory performance in both MWM and PA tests. Moreover, rolipram reversed the Aβ-induced increases in serum corticosterone (CORT), corticotropin-releasing factor, and glucocorticoid receptors (CRF-R and GR) levels, whereas it decreases in brain-derived neurotropic factor (BDNF) and the ratio of pCREB to CREB expression. These effects of rolipram were prevented by pre-treatment with PKA inhibitor H89. The findings indicated that the protective effects of rolipram against Aβ1-42-induced memory deficits might involve HPA axis and cAMP-CREB-BDNF signaling.
10.3389/fnagi.2018.00204
Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets.
Canet Geoffrey,Hernandez Célia,Zussy Charleine,Chevallier Nathalie,Desrumaux Catherine,Givalois Laurent
Frontiers in aging neuroscience
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has important health and economic impacts in the elderly. Despite a better understanding of the molecular mechanisms leading to the appearance of major pathological hallmarks (), effective treatments are still lacking. Sporadic AD forms () are multifactorial, and a panoply of risk factors have been identified. While the major risk factor is aging, growing evidence suggests that chronic stress or stress-related disorders increase the probability to develop AD. An early dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis or stress axis) has been observed in patients. The direct consequence of such perturbation is an oversecretion of glucocorticoids (GC) associated with an impairment of its receptors (glucocorticoid receptors, GR). These steroids hormones easily penetrate the brain and act in synergy with excitatory amino acids. An overexposure could be highly toxic in limbic structures () and contribute in the cognitive decline occurring in AD. GC and GR dysregulations seem to be involved in lots of functions disturbed in AD and a vicious cycle appears, where AD induces HPA axis dysregulation, which in turn potentiates the pathology. This review article presents some preclinical and clinical studies focusing on the HPA axis hormones and their receptors to fight AD. Due to its primordial role in the maintenance of homeostasis, the HPA axis appears as a key-actor in the etiology of AD and a prime target to tackle AD by offering multiple angles of action.
10.3389/fnagi.2019.00269
Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer's disease.
Lanté Fabien,Chafai Magda,Raymond Elisabeth Fabienne,Pereira Ana Rita Salgueiro,Mouska Xavier,Kootar Scherazad,Barik Jacques,Bethus Ingrid,Marie Hélène
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.
10.1038/npp.2015.25
Catalpol regulates function of hypothalamic-pituitary-adrenocortical-axis in an Alzheimer's disease rat model.
Wang Jin-Hong,Li Wen-Tao,Yu Shu-Tian,Xie Hai,Han Hui-Rong
Die Pharmazie
AIMS:To investigate the regulating effects of catalpol on the hypothalamic-pituitary- adrenocortical-axis (HPA) in an Alzheimer's disease (AD) rat model. METHODS:Healthy male Wistar Rats were selected. The AD model was generated by orthotopic injection of beta-amyloid 25-35 (Abeta25-35) into the right lateral ventricle. The animals were divided into five study groups: Catalpol at low dose (5 mg/kg), Catalpol at high dose (10 mg/kg), model control group and sham surgery control group, n = 9 respectively. The serum concentration of hydrocortisone (HYD), adrenocorticotropin (ACTH) and corticotropin releasing hormone (CRH) determined by Enzyme-Linked Immunosorbent Assay (ELISA). Structural alterations of the hypothalamus were examined by H&E stain and electron microscope. The CRH receptor 1 (CRHR1) positive neurons were detected with immunohistochemistry. RESULTS:Serum HYD level was significantly increased (p < 0.01), and both ACTH and CRH were dramatically decreased (p < 0.01) in the AD model group rats compared with normal control rats at day 7. Catalpol treatment was able to improve the hormone secretion disorder in AD model group rats compared with the model group (p < 0.01 or p < 0.05) in particular at 21 days. Structure damage of hypothalamus in the AD rat as evidenced less CRHR1 positive neurons, rough endoplasmic reticulum dilation and degranulation, and mitochondrial swelling under electron microscope. Catalpol treatment at both high and low doses was able to alleviate the structure damage of the hypothalamus in the AD rats. CONCLUSIONS:Catalpol could improve the endocrine function of the HPA and alleviate the structural damage of hypothalamus in AD rats.
Glucocorticoid receptors signaling impairment potentiates amyloid-β oligomers-induced pathology in an acute model of Alzheimer's disease.
Canet Geoffrey,Pineau Fanny,Zussy Charleine,Hernandez Célia,Hunt Hazel,Chevallier Nathalie,Perrier Véronique,Torrent Joan,Belanoff Joseph K,Meijer Onno C,Desrumaux Catherine,Givalois Laurent
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid-β oligomers (oAβ), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation. We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oAβ impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oAβ potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of the HPA axis and a feed-forward effect on PFC GR sensitivity could participate in the etiology of AD, in perturbing Aβ and Tau homeostasis. These results also reinforce the therapeutic potential of sGRm in AD.
10.1096/fj.201900723RRR
Anxiolytic impact of Apelin-13 in a rat model of Alzheimer's disease: Involvement of glucocorticoid receptor and FKBP5.
Aminyavari Samaneh,Zahmatkesh Maryam,Khodagholi Fariba,Sanati Mehdi
Peptides
Apelin-13 is known to be one of the predominant neuropeptides with marked protective role in circuits involved in mood disturbances. The most putative hypothesis in pathophysiology of Alzheimer's disease (AD) is Amyloid beta (Aβ) aggregation which interrupt proper function of hypothalamic-pituitary-adrenal (HPA) axis and are associated with anxiety. Here, we assessed the potential anxiolytic effect of Apelin-13 in a rodent cognitive impairment model induced by intrahippocampal Aβ 25-35 administration. We evaluated the memory impairment and anxiogenic behavior using shuttle box and Elevated plus maze apparatuses. We also measured the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP5) expression as important markers showing the proper feedback mechanism within the HPA axis. Our findings showed that Aβ 25-35 administration induced memory impairment and anxiety behaviors. Apelin-13 exerted the anxiolytic effects and provided protection against Aβ 25-35 -induced passive avoidance memory impairment. Moreover, Apelin-13 caused an increase in GR and a decrease in FKBP5 expression levels in Aβ 25-35 treated animals. Taken together, these findings showed the anxiolytic effect of Apelin-13. This effect at least in part, may be mediated through the regulation of GR and FKBP5 expression levels which have a pivotal role in the appropriate negative feedback mechanism within the HPA axis. These data suggest that Apelin-13 might be considered as a potential neuropeptide defense that reduces anxiety along with neuroprotective effect against the Aβ 25-35 -induced injury.
10.1016/j.peptides.2019.170102
Deregulation of hypothalamic-pituitary-adrenal axis functions in an Alzheimer's disease rat model.
Brureau Anthony,Zussy Charleine,Delair Brice,Ogier Charline,Ixart Guy,Maurice Tangui,Givalois Laurent
Neurobiology of aging
Elevated cortisol evidence in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids are involved in the development and/or maintenance of AD. We investigated the hypothalamic-pituitary-adrenal (HPA) axis activity, functionality, and reactivity for up to 6 weeks after an intracerebroventricular injection of amyloid-β(25-35) peptide (Aβ(25-35)) in rat, a validated acute model of AD. Aβ(25-35) induces memory impairment, alteration of anxiety responses, HPA axis hyperactivity, and glucocorticoid (GR) and mineralocorticoid (MR) receptor increases in brain regions related to HPA axis functions. GR are progressively translocated in neurons nucleus, while membrane version of MR is evidenced in all structures considered. The MR/GR ratio was modified in all structures considered. Aβ(25-35) induces a subtle disturbance in the feedback of the HPA axis, without modifying its functionality. The reactivity alteration is long-lasting, suggesting that amyloid toxicity affects the HPA axis adaptive response to stress. These findings are evidence of progressive HPA axis deregulation after Aβ(25-35), which is associated with an imbalance of MR/GR ratio and a disruption of the glucocorticoid receptors nucleocytoplasmic shuttling, and suggest that elevated glucocorticoids observed in AD could be first a consequence of amyloid toxicity.
10.1016/j.neurobiolaging.2012.11.015
3,4-Dihydroxyphenylethanol Assuages Cognitive Impulsivity in Alzheimer's Disease by Attuning HPA-Axis via Differential Crosstalk of α7 nAChR with MicroRNA-124 and HDAC6.
ArunSundar Mohanasundaram,Shanmugarajan Thukani Sathanantham,Ravichandiran Velayutham
ACS chemical neuroscience
Cognitive impulsivity, a form of suboptimal cost-benefit decision making, is an illustrious attribute of an array of neurodegenerative diseases including Alzheimer's disease (AD). In this study, a delay discounting paradigm was used to assess the effect of 3,4-dihydroxyphenylethanol (DOPET) on cognitive impulsivity, in an oA42i (oligomeric amyloid β plus ibotenic acid) induced AD mouse model, using a nonspatial T-maze task. The results depicted that oA42i administration elevated cognitive impulsivity, whereas DOPET treatment attenuated the impulsive behavior and matched the choice of the sham-operated controls. In addition, DOPET treatment has ameliorated the anxiety-like behavior in the oA42i-challenged mice. Probing the molecular signaling cascades underpinning these functional ramifications in the oA42i-challenged mice revealed reduced cholinergic (α7 nAChR; alpha 7 nicotinic acetylcholine receptor) function, dysregulated hypothalamic-pituitary-adrenal (HPA) axis (manifested by amplified glucocorticoid receptor expression and plasma corticosterone levels), and also aberrations in the neuroepigenetic (microRNA-124, HDAC6 (histone deacetylase 6), and HSP90 (heat-shock protein 90) expressions) as well as nucleocytoplasmic (importin-α1 expression and nuclear ultra-architecture) continuum. Nonetheless, DOPET administration ameliorated these perturbations and the observations were in line with that of the sham-operated mice. Further validation of the results with organotypic hippocampal slice cultures (OHSCs) confirmed the in vivo findings. We opine that HPA-axis attunement by DOPET might be orchestrated through the α7 nAChR-mediated pathway. Based on these outcomes, we posit that 3,4-dihydroxyphenylethanol might be a potential multimodal agent for the management of cognitive impulsivity and neuromolecular quagmire in AD.
10.1021/acschemneuro.7b00532
Akebia saponin D reverses corticosterone hypersecretion in an Alzheimer's disease rat model.
Wang Yuhui,Shen Jinyang,Yang Xiaolin,Jin Ye,Yang Zhonglin,Wang Rufeng,Zhang Fuming,Linhardt Robert J
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
BACKGROUND:Glucocorticoid hormones are implicated in the pathogenesis of Alzheimer's disease (AD) and other diseases including diabetes, hyperlipidemia, and osteoporosis. Akebia saponin D (ASD) possesses numerous pharmacological activities, including as an anti-AD, anti-hyperlipidemia, anti-diabetes, and anti-osteoporosis agent. The anti-AD effect of ASD is possibly through its regulation of glucocorticoid levels. PURPOSE:The present study was undertaken to investigate the neuroprotective effects of ASD on Aβ-induced cognitive deficits and to elucidate its underlying mechanism of action. METHODS:The AD rat model was established by an intracerebroventricular injection of Aβ into the lateral ventricles. Spatial learning and anxiety state were assessed by Morris water maze task and elevated plus-maze assay, respectively. The degree of hypertrophy of adrenal gland was analyzed using the viscera coefficient. Corticosterone and ACTH concentrations in the plasm were measured using biochemical assay kits. The activity of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1) in liver and groin fat pad was assessed by measuring cortisol production. RESULTS:Compared with the control group, AD rats displayed significant spatial learning and reference memory impairments, serious anxiety disorders, obvious hypertrophy of adrenal gland, elevated corticosterone and ACTH levels in the plasma, and increased 11β-HSD1 activity in liver and groin fat pad. ASD could significantly ameliorate the memory deficits and anxiety symptoms, markedly reduce the viscera coefficient of adrenal gland, observably decrease corticosterone and ACTH concentrations, and showed no effect on the activity of 11β-HSD1. CONCLUSIONS:These results indicate that ASD might exert a significant neuroprotective effect on cognitive impairment, driven in part by reducing systemic corticosterone level by down-regulation of the hypothalamic-pituitary-adrenal (HPA) axis.
10.1016/j.biopha.2018.07.149
Noise exposure accelerates the risk of cognitive impairment and Alzheimer's disease: Adulthood, gestational, and prenatal mechanistic evidence from animal studies.
Jafari Zahra,Kolb Bryan E,Mohajerani Majid H
Neuroscience and biobehavioral reviews
This review examines the adverse impacts of different noise exposure paradigms on the neuroendocrine system, hippocampal and neocortical structures, cognitive performances, and the development of Alzheimer's disease (AD)-like neuropathological changes in the brain of laboratory animals. Studies were reviewed in three periods during the lifespan including: adult animals exposed to noise, female rodents exposed to noise during gestation, and offspring exposed to noise during the prenatal period. Findings imply that chronic noise exposure dysregulates the neuroendocrine system leading to hyperactivation of the sympathetic divisions of the autonomic nervous system (i.e., the hypothalamic-pituitary-adrenal (HPA)-axis), and increases stress hormones that affect brain and behaviour. Enduring dysregulation of the HPA-axis was the most discussed mechanism for the harmful effect of noise during the lifespan. Studies also suggest a causative association of noise with diverse indicators of the AD-like neuropathology in rodents and a hypersusceptibility in females. The results indicate the importance of future neuroimaging studies to quantify the potential contribution of noise in predisposing cognitive decline and preclinical signs of dementia in humans.
10.1016/j.neubiorev.2019.04.001
Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer's Disease.
Ahmad Mir Hilal,Fatima Mahino,Mondal Amal Chandra
Neuropsychobiology
Alzheimer's disease (AD), the commonest progressive neurodegenerative disorder of the brain, is clinically characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies suggest a relationship between the endocrinal dysregulation and the neuronal loss during the AD pathology. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis regulating circulating levels of glucocorticoid hormones has been implicated in the pathophysiology of AD. Likewise, dysregulated insulin signaling, impaired glucose uptake and insulin resistance are some of the prime factors in the onset/progression of AD. In this review, we have discussed the changes in HPA and HPG axes, implicated insulin resistance/signaling and glucose regulation during the onset/progression of AD. Therefore, simultaneous detection of these endocrinal markers in the early or presymptomatic stages may help in the early diagnosis of AD. This evidence for implicated endocrinal functions supports the fact that modulation of endocrinal pathways can be used as therapeutic targets for AD. Future studies need to determine how the induction or inhibition of endocrinal targets could be used for predictable neuroprotection in AD therapies.
10.1159/000495521
Gut microbiota mediated allostasis prevents stress-induced neuroinflammatory risk factors of Alzheimer's disease.
Westfall Susan,Iqbal Umar,Sebastian Maria,Pasinetti Giulio Maria
Progress in molecular biology and translational science
The amyloid hypothesis of Alzheimer's disease (AD) has become outdated as researchers and clinicians recognize that lifestyle factors and environmental stressors have a greater impact on the etiology of AD than genetic predispositions. When persistent over decades, chronic psychological and physical stressors disrupt the body's natural adaptions to stress (allostasis) resulting in a general "wear and tear" on the body termed allostatic overload. Allostatic overload results in hypercortisolemia, disrupted hypothalamic-pituitary-adrenal (HPA) axis regulation, elevated proinflammatory cytokines and chemokines, reduced synaptic plasticity, persistently activated microglia, and importantly, a dysbiotic gut microbiota. This plethora of physiological maladaptations precedes the canonical symptoms of AD, including amyloid-beta plaque accumulation and tau hyperphosphorylation, indicating that a successful therapeutic approach to AD must first alleviate these risk factors. In this chapter, the use of gut microbiota modifying synbiotics, a combination of probiotics and prebiotics, to simultaneously and sustainably alleviate stress-induced AD risk factors is proposed. Synbiotic-derived bioactive metabolites can increase the integrity of the gut epithelial barrier preventing the infiltration of bacterial peptides and other immune-activating substances. These metabolites can also alter the balance of peripheral immune cells toward an anti-inflammatory state, protecting the body against stress-induced inflammatory challenges. These peripheral adaptations ultimately promote cognitive resilience to stress-induced AD by preventing microglia inflammasome activation, reinstating HPA axis negative feedback loops and allowing healthy neurogenic and neuroplasticity processes to ensue. Overall, synbiotics provide a novel treatment paradigm for AD that promote a sustainable allostasis to chronic stress, protecting the brain from the neuropathologies driving AD.
10.1016/bs.pmbts.2019.06.013
ATP-sensitive potassium-channel inhibitor glibenclamide attenuates HPA axis hyperactivity, depression- and anxiety-related symptoms in a rat model of Alzheimer's disease.
Esmaeili Mohammad Hossein,Bahari Behnam,Salari Ali-Akbar
Brain research bulletin
Affective disorders including depression and anxiety are among the most prevalent behavioral abnormalities in patients with Alzheimer's disease (AD), which affect the quality of life and progression of the disease. Dysregulation of the hypothalamic-pituitary-adrenal-(HPA) axis has been reported in affective disorders and AD. Recent studies revealed that current antidepressant drugs are not completely effective for treating anxiety- and depression-related disorders in people with dementia. ATP-sensitive-potassium-(K) channels are well-known to be involved in AD pathophysiology, HPA axis function and the pathogenesis of depression and anxiety-related behaviors. Thus, targeting of K channel may be a potential therapeutic strategy in AD. Hence, we investigated the effects of intracerebroventricular injection of Aβ25-35 alone or in combination with glibenclamide, K channel inhibitor on depression- and anxiety-related behaviors as well as HPA axis response to stress in rats. To do this, non-Aβ25-35- and Aβ25-35-treated rats were orally treated with glibenclamide, then the behavioral consequences were assessed using sucrose preference, forced swim, light-dark box and plus maze tests. Stress-induced corticosterone levels following forced swim and plus maze tests were also evaluated as indicative of abnormal HPA-axis-function. Aβ25-35 induced HPA axis hyperreactivity and increased depression- and anxiety-related symptoms in rats. Our results showed that blockade of K channels with glibenclamide decreased depression- and anxiety-related behaviors by normalizing HPA axis activity in Aβ25-35-treated rats. This study provides additional evidence that Aβ administration can induce depression- and anxiety-like symptoms in rodents, and suggests that K channel inhibitors may be a plausible therapeutic strategy for treating affective disorders in AD patients.
10.1016/j.brainresbull.2018.01.001