Schisantherin A Improves the Learning and Memory by Reducing the Phosphorylation of Tau Protein of the Hippocampus in AD Mice

Memory disorders are the main symptoms of aging and Alzheimer’s disease and seriously affect the quality of life. Schisandra, as a famous traditional Chinese medicine, has been used for modulating “the internal organs” for a thousand years. The total lignans from Schisandra have been scientifically proved to improve learning and memory ability. Since it is unclear which monomer in Schisandra total lignans exerts such a function, we evaluated the potential effects of Schisantherin A (SCA), the main monomer from Schisandra, on improving learning ability and memory in amyloid β-protein (Aβ1-42)-induced Alzheimer’s disease (AD) model mice. We found that SCA (5 mg/kg) significantly prolonged the latency and reduced the number of errors in a step-through test. SCA significantly shortened the time of finding the platform and increased the number of crossing the platform and the residence time in a Morris water maze test. SCA increased superoxide dismutase activities and reduced the Malondialdehyde level of the hippocampal tissue, suggesting its role in reducing oxidative stress in the AD mice. Furthermore, we found that SCA significantly decreased the hyperphosphorylation of Tau by altering glycogen synthase kinase-3β (GSK-3β) phosphorylation on Tyr216 and Ser9. Our results revealed the mechanism underlying SCA-mediated learning and memory improvement by regulating GSK-3β activity and lowering the hyperphosphorylation of Tau protein in the hippocampus of AD mice.

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Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.16.9637 ◽

1998 ◽

Vol 95 (16) ◽

pp. 9637-9641 ◽

Cited By ~ 275

Author(s):

Akihiko Takashima ◽

Miyuki Murayama ◽

Ohoshi Murayama ◽

Toshiyuki Kohno ◽

Toshiyuki Honda ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Amyloid Β ◽

Glycogen Synthase Kinase ◽

Presenilin 1 ◽

Amyloid Β Protein ◽

Glycogen Synthase Kinase 3Β ◽

Β Protein ◽

Gsk 3Β

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer’s disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid β protein (Aβ1–42). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3β (GSK-3β). Deletion studies show that both tau and GSK-3β bind to the same region of PS1, residues 250–298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3β into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3β. Mutations in PS1 that cause Alzheimer’s disease increase the ability of PS1 to bind GSK-3β and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3β with mutant PS1 leads to increased phosphorylation of tau.

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Traditional Chinese Medicine Huannao Yicong Decoction Extract Decreases Tau Hyperphosphorylation in the Brain of Alzheimer’s Disease Model Rats Induced by Aβ1–42

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/6840432 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Yu Cao ◽

Xingxing Jia ◽

Yun Wei ◽

Meixia Liu ◽

Jiangang Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Kinase ◽

Learning And Memory ◽

Tau Protein ◽

Glycogen Synthase ◽

Spatial Learning And Memory ◽

High Dose ◽

Tau Hyperphosphorylation ◽

Tau Protein Kinase

Objective. Huannao Yicong Decoction (HYD,还脑益聪方) has been shown to improve the learning and memory capabilities of Alzheimer’s disease (AD) subjects. However, the underlying mechanism remains to be determined.Methods. Sixty Sprague-Dawley rats were divided equally and randomly into five different groups including control, positive control, and HYD granules of low dose, medium dose, and high dose by daily gavage. The sham-treated rats were also given the same volume of sterile water by gavage. Twelve SD rats were treated with the same amount of physiological saline. Twelve weeks later, learning and memory capabilities, Aβcontent of the right brain and the expression of glycogen synthase kinase-3β(GSK-3β), total tau protein kinase (TTBK1), and cyclin-dependent kinase-5 (CDK-5) were tested.Results. Our results showed that high dose HYD treatment significantly improved the learning and memory capability of the AD rats and decreased the expression of TTBK1, GSK-3β, and CDK-5 in the hippocampal CA1 region.Conclusions. HYD treatment for 12 weeks significantly improved spatial learning and memory and effectively inhibited Aβdeposition, likely via reducing tau protein kinase expression and thus tau hyperphosphorylation and inflammatory injury. Taken together, these results suggest that HYD could be an effective treatment for AD.

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Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200106125910 ◽

2020 ◽

Vol 20 (12) ◽

pp. 1059-1073 ◽

Cited By ~ 3

Author(s):

Ahmad Abu Turab Naqvi ◽

Gulam Mustafa Hasan ◽

Md. Imtaiyaz Hassan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Glycogen Synthase ◽

Paired Helical Filaments ◽

Tau Hyperphosphorylation ◽

Microtubule Stabilization ◽

Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

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Morris Water Maze Test for Learning and Memory Deficits in Alzheimer's Disease Model Mice

Journal of Visualized Experiments ◽

10.3791/2920 ◽

2011 ◽

Cited By ~ 96

Author(s):

Kelley Bromley-Brits ◽

Yu Deng ◽

Weihong Song

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Morris Water Maze ◽

Water Maze ◽

Disease Model ◽

Memory Deficits ◽

Morris Water Maze Test ◽

Maze Test ◽

Learning And Memory Deficits

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Nrf2 Ablation Promotes Alzheimer’s Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3050971 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Peng Ren ◽

Jingwei Chen ◽

Bingxuan Li ◽

Mengzhou Zhang ◽

Bei Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Learning And Memory ◽

Spatial Learning ◽

Morris Water Maze Test ◽

Spatial Learning And Memory ◽

Related Factor ◽

Qrt Pcr

Introduction. Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Accumulating evidence has revealed that the slow progressive deterioration of AD is associated with oxidative stress and chronic inflammation in the brain. Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2), which acts through the Nrf2/ARE pathway, is a key regulator of the antioxidant and anti-inflammatory response. Although recent data show a link between Nrf2 and AD-related cognitive decline, the mechanism is still unknown. Thus, we explored how Nrf2 protects brain cells against the oxidative stress and inflammation of AD in a mouse model of AD (APP/PS1 transgenic (AT) mice) with genetic removal of Nrf2. Methods. The spatial learning and memory abilities of 12-month-old transgenic mice were evaluated using a Morris water maze test. Hippocampal levels of Nrf2, Aβ, and p-tauS404 and of astrocytes and microglia were determined by immunostaining. Inflammatory cytokines were determined by ELISA and quantitative real-time polymerase chain reaction (qRT-PCR). Oxidative stress was measured by 8-hydroxydeoxyguanosine immunohistochemistry, and the antioxidant response was determined by qRT-PCR. Results. The spatial learning and memory abilities of AT mice were impaired after Nrf2 deletion. Aβ and p-tauS404 accumulation was increased in the hippocampus of AT/Nrf2-KO mice. Astroglial and microglial activation was exacerbated, followed by upregulation of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. Conclusion. Our present results show that Nrf2 deficiency aggravates AD-like pathology in AT mice. This phenotype was associated with increased levels of oxidative and proinflammatory markers, which suggests that the Nrf2 pathway may be a promising therapeutic target for AD.

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Virtual Screening in Chinese Herbs with Multi-Target Effect on Alzheimer's Disease

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.765-767.256 ◽

2013 ◽

Vol 765-767 ◽

pp. 256-260

Author(s):

Yan Ling Zhang ◽

Yuan Ming Wang ◽

Yan Jiang Qiao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Virtual Screening ◽

Glycogen Synthase ◽

Chinese Herbs ◽

Multiple Targets ◽

Active Compounds ◽

Ache Inhibitors ◽

Gsk 3Β ◽

Pharmacophore Models

Multiple targets which closely related to Alzheimer's disease (AD) pathogenesis were selected for pharmacophore models generation and virtual screening in Chinese herbs. The targets comprised Acetylcholinesterase (AchE), muscarinic receptor 1 (M1), γ-secretase and glycogen synthase kinase 3β (GSK-3β). The pharmacophore models, which of AchE inhibitors, M1 agonists, γ-secretase inhibitors and GSK-3β inhibitors, were constructed by distance comparison method. Four testing databases for the evaluation of pharmacophore models were constructed with the active compounds with clearly marked activity on each target. The metric CAI (Comprehensive Appraisal Index) was then used to evaluate and obtain the best pharmacophore models of each target, which were then applied to screen the Traditional Chinese Medicine Database for potential active compounds in Chinese herbs. Four common used herbs were obtained, which contain the active compounds and can act on multiple targets, and were expected to have multiple activity of anti-AD disease.

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The relationship of diabetes mellitus with Alzheimer’s disease: a literature review

10.5327/1516-3180.280 ◽

2021 ◽

Author(s):

Fábio Dias Nogueira ◽

Ana Klara Rodrigues Alves ◽

Barbara Beatriz Lira da Silva ◽

Ana Kamila Rodrigues Alves ◽

Marlilia Moura Coelho Sousa ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Potential Link ◽

The Central Nervous System ◽

Gsk 3Β ◽

Type 3 ◽

The Brain

Introduction: Alzheimer’s disease (AD) is closely related to diabetes mellitus (DM), and AD is also considered to be type 3 diabetes (T3D). Glycogen synthase kinase-3β (GSK-3β) may be the potential link between DM and AD. GSK-3β is one of the main factors that lead to insulin deficiency and insulin resistance, and insulin resistance is a characteristic of the development of DM. In AD, GSK-3β plays an important role in hyperphosphorylation of the tau protein (tau) associated with microtubules, which is one of the pathological features in AD. Objective: To analyze DM as a factor for the development of AD. METHODOLOGY: This is an integrative review of the literature, which is a construction of a comprehensive analysis of the literature with pre-defined steps, carried out through PubMed, 1.501 articles were found, of which 10 were selected, through the simultaneous crossing between the descriptors “Diabetes mellitus”, “Alzheimer “. Articles written in Portuguese and English published between 2016 and 2021 were inserted. Results: DM associated with insulin resistance affects psychomotor efficiency, attention, learning memory, mental flexibility, speed and executive function of the brain, thus being an independent risk factor for cognitive impairment and damage to the central nervous system, hyperglycemia, which can cause increased oxidative stress leading to progressive functional and structural abnormalities in the brain. Conclusion:The risk of dementia in patients with DM is higher than in nondiabetic patients and it is also well known that DM2 / insulin resistance is involved in AD.

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Ameliorative effects of olibanum essential oil on learning and memory in Aβ1-42-induced Alzheimer’s disease mouse model

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i8.12 ◽

2020 ◽

Vol 19 (8) ◽

pp. 1643-1651

Author(s):

Zhenzhen Zhang ◽

Wenhua Chen ◽

Jie Luan ◽

Dagui Chen ◽

Lina Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Essential Oil ◽

Learning And Memory ◽

Hippocampal Neurons ◽

Amyloid Β ◽

Amyloid Plaques ◽

Morris Water Maze Test ◽

Amyloid Β Peptide ◽

Brain Tissues

Purpose: To study the effect of olibanum essential oil (OEO) on learning and memory in Alzheimer’s disease (AD) mouse.Methods: Mice were administered the 42-amino acid form of amyloid β-peptide (Aβ1-42) to induce AD and then treated with OEO at 150, 300, and 600 mg/kg, p.o. for two weeks. Following treatment, the AD mice were assessed by step-down test (SDT), dark avoidance test (DAT), and Morris water maze test (MWM). Blood and brain tissues were collected for biochemical assessments. Gas chromatographymass spectroscopy was used to analyze the main constituents of OEO.Results: The main constituents of OEO were limonene, α-pinene, and 4-terpineol. Treatment with OEO prolonged t latency in SDT and DAT, but decreased error times. Escape latency decreased and crossing times were rose in the MWM following OEO treatment (p < 0.5). Treatment with OEO also enhanced the acetylcholine levels and decreased the acetylcholinesterase levels in serum and brain tissue (p < 0.5). Additionally, OEO reduced amyloid plaques in the hippocampus and protected hippocampal neurons from damage. Furthermore, OEO decreased c-fos expression in hippocampus tissues from AD mice (p < 0.5).Conclusion: OEO has significant ameliorative effect AD-induced deterioration in learning and memory in AD mouse induced by Aβ1-42. The mechanisms of these effects are related to increased acetylcholine contents, reduction of amyloid plaques, protection of hippocampal neurons, and downregulation of c-fos in brain tissues. The results justify the need for further investigation of candidate drugs derived from OEO for the management of AD. Keywords: Olibanum, Essential oil, Learning, Memory, AD

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Lentivirus-Carried microRNA-195 Rescues Memory Deficits of Alzheimer’s Disease Transgenic Mouse by Attenuating the Generation of Amyloid Plaques

Frontiers in Pharmacology ◽

10.3389/fphar.2021.633805 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dan Su ◽

Yani Chai ◽

Junkai Yang ◽

Xuqiao Wang ◽

Ying Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Learning And Memory ◽

Transgenic Mouse ◽

New Drugs ◽

Learning Ability ◽

Gain Of Function ◽

Memory Ability ◽

Bace1 Level

Although lots of new drugs are developed to treat Alzheimer’s disease (AD), many clinical trials of monotherapy have failed to affect disease progression or symptoms compared with placebo. Recently, scientists believe that combination treatment is more promising than monotherapy. Previous studies found that microRNA-195 (miR-195) was down-regulated in the hippocampi and cortices of chronic brain hypoperfusion (CBH) rats and ApoE4(+/+) mice, and up-regulation of miR-195 can improve the declined cognitive function of ApoE4(+/+) mice and CBH rats by targeting multi-genes that are related to AD pathology, including amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) genes. However, whether the gain-of-function of miR-195 could improve the impaired learning and memory ability of APP/PS1 transgenic mouse has not been reported. In this study, we stereotaxically injected lentiviral-carried miR-195 into the bilateral hippocampus of 4-month-old (4M) APP/PS1 mice. Morris water maze (MWM) was performed to detect the effect of miR-195 on the cognitive function of APP/PS1 mice after 1M, 2M, and 3M treatment. Western blot was used to detect the expression of APP, BACE1, and AT8. Aβ plagues were quantitatively assessed by immunofluorescence technique. We found that the declined cognitive phenotype of APP/PS1 mice occurred at the age of 6M, not at the age of 5M. And treatment of Lv-pre-miR-195 to APP/PS1 mice for 1M did not achieve any changes. Although Lv-pre-miR-195 treatment for 2M improved the declined learning ability of APP/PS1 mice, it did not affect the memory functions. However, Lv-pre-miR-195 treatment in APP/PS1 mice for 3M can effectively improve both the learning and memory ability of APP/PS1 mice at the age of 7M. Further studies demonstrated that gain-of-function of miR-195 by Lv-pre-miR-195 injection could inhibit the increased APP and AT8 expression of APP/PS1 mice but did not affect BACE1 level that was not changed in both hippocampus and cortex. By counting the number of Aβ plaques of different sizes, we found that Lv-pre-miR-195 treatment mainly reduced the number of Aβ plaques of less than 20 μm, but did not affect the number of Aβ plaques of greater than 50 μm. Taken together, the gain-of -function of miR-195 in the hippocampus can improve the cognition of APP/PS1 mice, probably by blocking the formation of Aβ plagues rather than clearing those that have already formed Aβ plagues.

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