scholarly journals Electroacupuncture Protects Cognition by Regulating Tau Phosphorylation and Glucose Metabolism via the AKT/GSK3β Signaling Pathway in Alzheimer’s Disease Model Mice

2020 ◽  
Vol 14 ◽  
Author(s):  
Anping Xu ◽  
Qingtao Zeng ◽  
Yinshan Tang ◽  
Xin Wang ◽  
Xiaochen Yuan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Metabolism ◽  
Cognitive Ability ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Disease Model ◽  
Tau Phosphorylation ◽  
Downstream Target ◽  
Abnormal Glucose Metabolism

BackgroundAlzheimer’s disease (AD) is mainly manifested as a continuous and progressive decline in cognitive ability. Neurofibrillary tangles (NFTs) are pathological hallmarks of AD and due to accumulated phosphorylated Tau. Glycogen synthase kinase-3β (GSK3β), as a major Tau kinase and a downstream target of the serine protein kinase B (AKT) signaling pathway, can regulate Tau phosphorylation in AD. Importantly, the AKT/GSK3β signaling pathway is involved in glucose metabolism, and abnormal glucose metabolism is found in the AD brain. Numerous studies have shown that electroacupuncture (EA), which is thought to be a potential complementary therapeutic approach for AD, can protect cognitive ability to a certain extent.ObjectiveThe purpose of this experiment was to investigate whether the protective and beneficial mechanism of EA on cognition was mediated by the AKT/GSK3β signaling pathway, thereby improving glucose metabolism and Tau phosphorylation in the brain.MethodsEA was applied to the Baihui (GV20) and Yintang (GV29) acupoints of 6-month-old amyloid precursor protein (APP)/presenilin-1 (PS1) mice for 20 min, and then quickly prick Shuigou (GV26) acupoint. The intervention was performed once every other day for 28 days. The Morris water maze (MWM) test was performed on C57BL/6N (Non-Tg) mice, APP/PS1 (Tg) mice and EA-treated Tg (Tg + EA) mice to evaluate the effect of EA therapy on cognitive function. 18F-FDG positron emission tomography (PET), immunohistochemistry, and western blotting (WB) were used to investigate the possible mechanism underlying the effect of EA on AD.ResultsEA treatment significantly improved the cognition of APP/PS1 mice and the glucose uptake rate in the hippocampus. Furthermore, EA inhibited the phosphorylation of Tau (Ser199 and Ser202) proteins by inducing AKT (Ser473) and GSK3β (Ser9) phosphorylation.ConclusionThese results demonstrate that EA intervention protects cognition by enhancing glucose metabolism and inhibiting abnormal phosphorylation of Tau protein in the AD model mice, and the AKT/GSK3β pathway might play an irreplaceable role in the regulation process.

Genipin Attenuates Tau Phosphorylation and Aβ Levels in Cellular Models of Alzheimer's Disease

2021 ◽  
Author(s):  
Meiting Li ◽  
Nan Cai ◽  
Liang Gu ◽  
Lijun Yao ◽  
Decheng Bi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Tau Phosphorylation ◽  
Brain Disorder ◽  
Cellular Models ◽  
Aβ Generation ◽  
Aβ Production

Abstract Alzheimer’s disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules are considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

scholarly journals Propranolol reduces cognitive deficits, amyloid β levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration

2013 ◽  
Vol 16 (6) ◽  
pp. 1351-1360 ◽  
Author(s):  
Marta Dobarro ◽  
Lourdes Orejana ◽  
Norberto Aguirre ◽  
Maria J. Ramírez
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Glycogen Synthase ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Object Recognition Test ◽  
Adrenergic Antagonist ◽  
Propranolol Treatment

Abstract Chronic exposure to glucocorticoids might result not only in insulin resistance or cognitive deficits, but it is also considered as a risk factor for pathologies such as Alzheimer's disease. Propranolol is a β-adrenergic antagonist commonly used in the treatment of hypertension or acute anxiety. The effects of propranolol (5 mg/kg) have been tested in a model of chronic corticosterone administration (100 µg/ml, 4 wk) in drinking water. Corticosterone administration led to cognitive impairment in the novel object recognition test that was reversed by propranolol. Increased levels of Aβ in the hippocampus of corticosterone-treated mice were counteracted by propranolol treatment, purportedly through an increased IDE expression. Chronic corticosterone treatment induced responses characteristic of insulin resistance, as increased peripheral insulin levels, decreased activation of the insulin receptor (pIR) and decreased associated intracellular pathways (pAkt). These effects might be related to a decreased c-Jun N terminal kinase 1 expression. Again, propranolol was able to counteract all corticosterone-induced effects. One of the main kinases involved in tau phosphorylation, glycogen synthase kinase 3β (GSK3β), which is inactivated by phosphorylation by pAkt, was found to be decreased after corticosterone and increased after propranolol treatment. Concomitant changes in pTau expression were found. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for pathologies associated with the interaction glucocorticoids-insulin resistance and the development of relevant cellular processes for Alzheimer's disease.

scholarly journals Neurodegenerative Pathways in Alzheimer’s Disease: A Review

2020 ◽  
Vol 18 ◽  
Author(s):  
Anu K R ◽  
Subham Das ◽  
Alex Joseph ◽  
G Gautham Shenoy ◽  
Angel Treasa Alex ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Senile Plaques ◽  
Symptomatic Relief ◽  
Wnt Signaling Pathway ◽  
Memory Loss ◽  
Current Therapy ◽  
Quality Life

: Alzheimer’s disease (AD) is a complex neurodegenerative disease which leads to insidious deterioration of brain function and is considered the sixth leading cause of death in the world. Alzheimer’s patients suffer from memory loss, cognitive deficit and behavioral changes; thus, they eventually follow a low-quality life. AD, considered as a multifactorial disorder involving different neuropathological mechanisms. Recent research has identified more than 20 pathological factors that are promoting disease progression. Three significant hypotheses are said to be the root cause of disease pathology, which include acetylcholine deficit, the formation of amyloid-beta senile plaques and tau protein hyperphosphorylation. Apart from these crucial factors, pathological factors such as apolipoprotein E (APOE), glycogen synthase kinase 3β, notch signaling pathway, Wnt signaling pathway, etc., are considered to play a role in the advancement of AD and therefore could be used as targets for drug discovery and development. As of today, there is no complete cure or effective disease altering therapies for AD. The current therapy is assuring only symptomatic relief from the disease, and progressive loss of efficacy for these symptomatic treatments warrants the discovery of newer drugs by exploring these novel drug targets. A comprehensive understanding of these therapeutic targets and their neuropathological role in AD is necessary to identify novel molecules for the treatment of AD rationally.

Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors

2020 ◽  
Vol 20 (17) ◽  
pp. 1522-1534 ◽  
Author(s):  
Pankaj Wadhwa ◽  
Priti Jain ◽  
Hemant R. Jadhav
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
High Specificity ◽  
Tau Phosphorylation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Important Target ◽  
The Brain

: Glycogen Synthase Kinase 3 (GSK3) is one of the Serine/Threonine protein kinases, which has gained a lot of attention for its role in a variety of pathways. It has two isoforms, GSK3α and GSK3β. However, GSK3β is highly expressed in different areas of the brain and has been implicated in Alzheimer’s disease as it is involved in tau phosphorylation. Due to its high specificity concerning substrate recognition, GSK3 has been considered as an important target. In the last decade, several GSK3 inhibitors have been reported and two molecules are in clinical trials. This review collates the information published in the last decade about the role of GSK3 in Alzheimer’s disease and progress in the development of its inhibitors. Using this collated information, medicinal chemists can strategize and design novel GSK3 inhibitors that could be useful in the treatment of Alzheimer’s disease.

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