scholarly journals Alpha 1-Antichymotrypsin, an Inflammatory Protein Overexpressed in the Brains of Patients with Alzheimer’s Disease, Induces Tau Hyperphosphorylation through c-Jun N-Terminal Kinase Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Ethika Tyagi ◽  
Tina Fiorelli ◽  
Michelle Norden ◽  
Jaya Padmanabhan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Interleukin 1 ◽  
Tau Phosphorylation ◽  
Primary Neurons ◽  
Tau Hyperphosphorylation ◽  
Kinase Activation ◽  
Inflammatory Protein ◽  
Jnk Inhibitors ◽  
Inflammatory Proteins

The association of inflammatory proteins with neuritic plaques in the brains of Alzheimer’s disease (AD) patients has led to the hypothesis that inflammation plays a pivotal role in the development of pathology in AD. Earlier studies have shown that alpha 1-antichymotrypsin (ACT) enhances amyloid beta fibrillization and accelerated plaque formation in APP transgenic mice. Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons. In order to understand the mechanisms by which inflammatory proteins enhance tau hyperphosphorylation, we injected interleukin-1β(IL-1β) intracerebroventricularly into mice expressing human ACT, human tau, or both transgenes. It was found that the hyperphosphorylation of tau in ACT and ACT/htau mice after IL-1βinjection correlated with increased phosphorylation of c-Jun N-terminal kinase (JNK). We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation. These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation-induced tau hyperphosphorylation and neurodegeneration associated with AD.

scholarly journals Epigenetic Modulation on Tau Phosphorylation in Alzheimer’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Chao-Chao Yu ◽  
Tao Jiang ◽  
Ao-Fei Yang ◽  
Yan-Jun Du ◽  
Miao Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Noncoding Rna ◽  
Pathological Change ◽  
Epigenetic Modification ◽  
Tau Phosphorylation ◽  
Research Progress ◽  
Tau Hyperphosphorylation ◽  
Rna Regulation ◽  
Epigenetic Modulation

Tau hyperphosphorylation is a typical pathological change in Alzheimer’s disease (AD) and is involved in the early onset and progression of AD. Epigenetic modification refers to heritable alterations in gene expression that are not caused by direct changes in the DNA sequence of the gene. Epigenetic modifications, such as noncoding RNA regulation, DNA methylation, and histone modification, can directly or indirectly affect the regulation of tau phosphorylation, thereby participating in AD development and progression. This review summarizes the current research progress on the mechanisms of epigenetic modification associated with tau phosphorylation.

scholarly journals Site-Specific Cerebrospinal Fluid Tau Hyperphosphorylation in Response to Alzheimer’s Disease Brain Pathology: Not All Tau Phospho-Sites are Hyperphosphorylated

2021 ◽  
pp. 1-15
Author(s):  
Nicolas R. Barthélemy ◽  
Balazs Toth ◽  
Paul T. Manser ◽  
Sandra Sanabria-Bohórquez ◽  
Edmond Teng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Phosphorylation ◽  
Amyloid Pet ◽  
Tau Hyperphosphorylation ◽  
Cross Sectional ◽  
Site Specific ◽  
Treatment Objective ◽  
Sectional Analysis ◽  
The Relationship

Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer’s disease (AD) diagnosis and treatment. Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal-amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients. Results: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with the SUVR measures from [18F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18F]GTP1 and amyloid PET. Conclusion: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease.

Escitalopram Alleviates Alzheimer’s Disease-Type Tau Pathologies in the Aged P301L Tau Transgenic Mice

2020 ◽  
Vol 77 (2) ◽  
pp. 807-819
Author(s):  
Yan-Juan Wang ◽  
Wei-Gang Gong ◽  
Qing-Guo Ren ◽  
Zhi-Jun Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Phosphorylation ◽  
Tau Hyperphosphorylation ◽  
Protective Effects ◽  
Protein Levels ◽  
Phosphorylated Akt ◽  
Biochemical Analyses ◽  
Gsk 3Β

Background: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer’s disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro. Objective: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. Methods: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. Results: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. Conclusion: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway.

scholarly journals PL - 028 Aerobic exercise inhibits tau hyperphosphorylation through activation of the PI3K/Akt pathway in the hippocampus of APP/PS1 mice

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Guoliang Fang ◽  
Jiexiu Zhao ◽  
Li Zhang ◽  
Pengfei Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Group ◽  
Aerobic Exercise ◽  
Water Maze ◽  
Tau Phosphorylation ◽  
Exercise Group ◽  
Akt Pathway ◽  
Tau Hyperphosphorylation ◽  
Sedentary Group

Objective Many studies suggest that regular physical exercise can reduce the risk of Alzheimer’s disease and slow its onset and progression. However, the exact mechanism is still unclear. Clinically, Alzheimer’s disease is characterized by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles, which are associated with amyloid-β and tau hyperphosphorylation respectively. The PI3K/Akt signaling pathway regulates tau phosphorylation and plays a pivotal role in the development of pathology in Alzheimer’s disease. Here we investigated the effects of aerobic exercise on tau phosphorylation and examined whether these effects were mediated by the PI3K/Akt pathway in the hippocampus of APP/PS1 transgenic mice. Methods 40 male APP/PS1 transgenic mice were randomly divided into four groups: sedentary group (T-SE; n=10), exercise group (T-EX; n=10), sedentary with GNE-317 treatment group (T-SEG; n=10) and exercise with GNE-317 treatment group (T-EXG; n=10). GNE-317 is a potent and selective PI3K/Akt pathway inhibitor that can cross the blood-brain barrier and show effective suppression of Akt phosphorylation in the mice brain. The mice in the T-EX and T-EXG groups were given exercise training on a treadmill for 5 days/week for 8 weeks with 0% grade, and progressively ran from 30 min/day at 12 m/min, up to 60 min/day at 15 m/min. The mice in the T-SE and T-SEG groups were placed individually on another treadmill at 0 m/min for the same duration. 48 hours after the last exercise bout, all mice were intraperitoneally injected an anesthetic for inducing anesthesia, and the hippocampus were rapidly extracted. The protein and phosphorylation levels of tau, PI3K, Akt and GSK3β were assayed by Western blot and immunohistochemistry. The cognitive function were tested by morris water maze. Results We found out that 8 weeks of aerobic exercise reduced tau phosphorylation at multiple sites including Ser202, Thr231 and Ser396, and increased phosphorylation of Akt at Thr308 and Ser473 and of GSK3β at Ser9. Furthermore, in the morris water maze test, the exercise group showed a reduced escape time and distance compared with those of the sedentary group, suggesting that aerobic exercise improved learning and cognitive ability. While the above-mentioned results were attenuated in the PI3K/Akt inhibitor GNE-317 treatment groups. Conclusions Our study demonstrated that aerobic exercise could inhibit tau hyperphosphorylation and improve cognitive funtion through activation of the PI3K/Akt pathway in the hippocampus of APP/PS1 mice.

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

2020 ◽  
Vol 20 (12) ◽  
pp. 1059-1073 ◽  
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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