Diet control to achieve euglycaemia induces tau hyperphosphorylation via AMPK activation in the hippocampus of diabetic rats

2020 ◽  
Vol 11 (1) ◽  
pp. 339-346
Author(s):  
Dong Jun Sung ◽  
Yun-Hee Noh ◽  
Jun-Ho Lee ◽  
Mingli Jin ◽  
Jin-Seoung Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Neurodegenerative Disease ◽  
Neurofibrillary Tangles ◽  
Diabetic Rats ◽  
Hyperphosphorylated Tau ◽  
Tau Hyperphosphorylation ◽  
Ampk Activation ◽  
Pathologic Findings ◽  
Diet Control ◽  
Tau Aggregation

Alzheimer's disease (AD) is a chronic neurodegenerative disease, and typical pathologic findings include abnormally hyperphosphorylated tau aggregation and neurofibrillary tangles.

scholarly journals Diet Control to Achieve Euglycemia Induces Tau Hyperphosphorylation Via AMPK Activation in the Hippocampus of Diabetic Rats

2018 ◽  
Author(s):  
Sang-Don Han ◽  
Jun-Ho Lee ◽  
Yun-Hee Noh ◽  
Mingli Jin ◽  
Jin-Seong Kim
Keyword(s):  
Tau Phosphorylation ◽  
Diabetic Rats ◽  
Ampk Activation ◽  
Important Indicator ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Strict Diet ◽  
Diet Control ◽  
Ampk Activity ◽  
Tau Aggregation

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, and typical pathologic findings include abnormally hyperphosphorylated tau aggregation and neurofibrillary tangles. Insulin resistance and hyperglycemia have been assessed as risk factors for AD development. As the maintenance of optimal blood glucose levels is an important indicator of diabetes mellitus (DM) treatment, diet control is essential. AMPK is a crucial sensor of cellular bioenergetics for controlling anabolic and catabolic metabolism. Diet restriction to achieve euglycemia can increase AMPK activity in the liver and heart. Since AMPK is a direct regulator of tau phosphorylation, we hypothesized that strict diet control to achieve euglycemia affects tau protein phosphorylation through increased AMPK activity in the hippocampus of DM rats. To confirm this hypothesis, we generated insulin-deficient DM rats by subtotal pancreatectomy. Animals were categorized into the restriction (R) group, control (C) group and ad libitum (AL) group according to the diet. We found that tau phosphorylation was significantly increased in the R group compared with the C or AL group. AMPK activity in the R group significantly increased compared to that of the C group or AL group, as expected. Furthermore, the R group showed more critical tau pathology in the hippocampus than the other groups. These results suggest that diet control to achieve euglycemia in insulin-deficient DM conditions is harmful because of the increased possibility of AD development through increased tau phosphorylation by AMPK activation in the hippocampus. We propose that not only hyperglycemia but also euglycemia, which is beneficial in DM patients, must be considered a potential risk factor for AD development, especially when euglycemia is achieved by diet control during insulin deficiency.

scholarly journals Amphiphysin I cleavage by asparagine endopeptidase leads to tau hyperphosphorylation and synaptic dysfunction

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Xingyu Zhang ◽  
Li Zou ◽  
Lanxia Meng ◽  
Min Xiong ◽  
Lina Pan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cognitive Deficits ◽  
Neurofibrillary Tangles ◽  
Molecular Mechanisms ◽  
Cysteine Proteinase ◽  
Tau Phosphorylation ◽  
Synaptic Dysfunction ◽  
Hyperphosphorylated Tau ◽  
Tau Hyperphosphorylation ◽  
Terminal Fragment

Neurofibrillary tangles composed of hyperphosphorylated tau and synaptic dysfunction are characteristics of Alzheimer’s disease (AD). However, the underlying molecular mechanisms remain poorly understood. Here, we identified Amphiphysin I mediates both tau phosphorylation and synaptic dysfunction in AD. Amphiphysin I is cleaved by a cysteine proteinase asparagine endopeptidase (AEP) at N278 in the brains of AD patients. The amount of AEP-generated N-terminal fragment of Amphiphysin I (1-278) is increased with aging. Amphiphysin I (1-278) inhibits clathrin-mediated endocytosis and induces synaptic dysfunction. Furthermore, Amphiphysin I (1-278) binds p35 and promotes its transition to p25, thus activates CDK5 and enhances tau hyperphosphorylation. Overexpression of Amphiphysin I (1-278) in the hippocampus of Tau P301S mice induces synaptic dysfunction, tau hyperphosphorylation, and cognitive deficits. However, overexpression of the N278A mutant Amphiphysin I, which resists the AEP-mediated cleavage, alleviates the pathological and behavioral defects. These findings suggest a mechanism of tau hyperphosphorylation and synaptic dysfunction in AD.

Seeding-Competent Tau in Gray Matter Versus White Matter of Alzheimer’s Disease Brain

2021 ◽  
Vol 79 (4) ◽  
pp. 1647-1659
Author(s):  
Ruozhen Wu ◽  
Jianlan Gu ◽  
Dingwei Zhou ◽  
Yunn Chyn Tung ◽  
Nana Jin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Gray Matter ◽  
Brain Regions ◽  
Hyperphosphorylated Tau ◽  
Tau Hyperphosphorylation ◽  
Brain Extracts ◽  
Axonal Compartment ◽  
Tau Aggregation

Background: Neurofibrillary pathology of abnormally hyperphosphorylated tau spreads along neuroanatomical connections, underlying the progression of Alzheimer’s disease (AD). The propagation of tau pathology to axonally connected brain regions inevitably involves trafficking of seeding-competent tau within the axonal compartment of the neuron. Objective: To determine the seeding activity of tau in cerebral gray and white matters of AD. Methods: Levels of total tau, hyperphosphorylation of tau, and SDS- and β-mercaptoethanol–resistant high molecular weight tau (HMW-tau) in crude extracts from gray and white matters of AD frontal lobes were analyzed by immuno-blots. Tau seeding activity was quantitatively assessed by measuring RIPA buffer–insoluble tau in HEK-293FT/tau151-391 cells treated with brain extracts. Results: We found a comparable level of soluble tau in gray matter versus white matter of control brains, but a higher level of soluble tau in gray matter than white matter of AD brains. In AD brains, tau is hyperphosphorylated in both gray and white matters, with a higher level in the former. The extracts of both gray and white matters of AD brains seeded tau aggregation in HEK-293FT/tau151–391 cells but the white matter showed less potency. Seeding activity of tau in brain extracts was positively correlated with the levels of tau hyperphosphorylation and HMW-tau. RIPA-insoluble tau, but not RIPA-soluble tau, was hyperphosphorylated tau at multiple sites. Conclusion: Both gray and white matters of AD brain contain seeding-competent tau that can template aggregation of hyperphosphorylated tau, but the seeding potency is markedly higher in gray matter than in white matter.

scholarly journals Diet Control Diet to Achieve Euglycemia Induces Tau Hyperphosphorylation Via AMPK Activation in the Hippocampus of Diabetic Rats

2018 ◽  
Author(s):  
Sang-Don Han ◽  
Jun-Ho Lee ◽  
Yun-Hee Noh ◽  
Mingli Jin ◽  
Jin-Seong Kim
Keyword(s):  
Control Diet ◽  
Tau Phosphorylation ◽  
Diabetic Rats ◽  
Ampk Activation ◽  
Important Indicator ◽  
Glucose Levels ◽  
Strict Diet ◽  
Diet Control ◽  
Ampk Activity ◽  
Tau Aggregation

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, and typical pathologic findings include abnormally hyperphosphorylated tau aggregation and neurofibrillary tangles. Insulin resistance and hyperglycemia have been assessed as risk factors for AD development. As the maintenance of optimal blood glucose levels is an important indicator of diabetes mellitus (DM) treatment, diet control is essential. AMPK is a crucial sensor of cellular bioenergetics for controlling anabolic and catabolic metabolism. Diet restriction to achieve euglycemia can increase AMPK activity in the liver and heart. Since AMPK is a direct regulator of tau phosphorylation, we hypothesized that strict diet control to achieve euglycemia affects tau protein phosphorylation through increased AMPK activity in the hippocampus of DM rats. To confirm this hypothesis, we generated insulin-deficient DM rats by subtotal pancreatectomy. Animals were categorized into the restriction (R) group, control (C) group and ad libitum (AL) group according to the diet. We found that tau phosphorylation was significantly increased in the R group compared with the C or AL group. AMPK activity in the R group significantly increased compared to that of the C group or AL group, as expected. Furthermore, the R group showed more critical tau pathology in the hippocampus than the other groups. These results suggest that diet control to achieve euglycemia in insulin-deficient DM conditions is harmful because of the increased possibility of AD development through increased tau phosphorylation by AMPK activation in the hippocampus. We propose that not only hyperglycemia but also euglycemia, which is beneficial in DM patients, must be considered a potential risk factor for AD development, especially when euglycemia is achieved by diet control during insulin deficiency.

scholarly journals Alzheimer’s disease brain contains tau fractions with differential prion-like activities

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Longfei Li ◽  
Ruirui Shi ◽  
Jianlan Gu ◽  
Yunn Chyn Tung ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cultured Cells ◽  
Regional Distribution ◽  
Proteinase K ◽  
Hyperphosphorylated Tau ◽  
Terminal Portion ◽  
Tau Pathology ◽  
Heat Stable ◽  
Tau Aggregation

AbstractNeurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer’s disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms. In the present study, we prepared different tau fractions by sedimentation combined with sarkosyl solubility from AD brains and analyzed their biochemical and pathological properties. We found that tau in oligomeric fraction (O-tau), sarkosyl-insoluble fractions 1 and 2 (SI1-tau and SI2-tau) and monomeric heat-stable fraction (HS-tau) showed differences in truncation, hyperphosphorylation, and resistance to proteinase K. O-tau, SI1-tau, and SI2-tau, but not HS-tau, were hyperphosphorylated at multiple sites and contained SDS- and β-mercaptoethanol–resistant high molecular weight aggregates, which lacked the N-terminal portion of tau. O-tau and SI2-tau displayed more truncation and less hyperphosphorylation than SI1-tau. Resistance to proteinase K was increased from O-tau to SI1-tau to SI2-tau. O-tau and SI1-tau, but not SI2-tau or HS-tau, captured tau from cell lysates and seeded tau aggregation in cultured cells. Heat treatment could not kill the prion-like activity of O-tau to capture normal tau. Hippocampal injection of O-tau into 18-month-old FVB mice induced significant tau aggregation in both ipsilateral and contralateral hippocampi, but SI1-tau only induced tau pathology in the ipsilateral hippocampus, and SI2-tau and HS-tau failed to induce any detectable tau aggregation. These findings suggest that O-tau and SI1-tau have prion-like activities and may serve as seeds to recruit tau and template tau to aggregate, resulting in the propagation of tau pathology. Heterogeneity of tau pathology within AD brain results in different fractions with different biological and prion-like properties, which may pose a major challenge in targeting tau for development of effective therapeutic treatments.

scholarly journals Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ1–42 synaptotoxicity

2017 ◽  
Vol 216 (10) ◽  
pp. 3161-3178 ◽  
Author(s):  
Xiaoyi Qu ◽  
Feng Ning Yuan ◽  
Carlo Corona ◽  
Silvia Pasini ◽  
Maria Elena Pero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Axonal Transport ◽  
Dendritic Spines ◽  
Posttranslational Modifications ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Driving Factors ◽  
Hyperphosphorylated Tau ◽  
Tau Hyperphosphorylation

Oligomeric Amyloid β1–42 (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

scholarly journals Porphyromonas gingivalis-Induced Neuroinflammation in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Ingar Olsen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Porphyromonas Gingivalis ◽  
Amyloid Beta ◽  
Neurofibrillary Tangles ◽  
Chronic Periodontitis ◽  
Cathepsin B ◽  
Hyperphosphorylated Tau ◽  
Protein Kinase R

“Chronic” periodontitis and its keystone pathogen Porphyromonas gingivalis have repeatedly been associated with Alzheimer’s disease (AD). Pathological hallmarks in AD are brain accumulations of amyloid-beta and neurofibrillary tangles consisting of aggregated and hyperphosphorylated tau. In addition, neuroinflammation induced by P. gingivalis has increasingly been recognized as a factor in the pathogenesis of AD. The present mini-review discusses possible mechanisms for the induction of neuroinflammation by P. gingivalis in AD, involving factors such as pro-inflammatory mediators, amyloid-beta, tau, microglia, cathepsin B, and protein kinase R. Inflammagens of P. gingivalis such as lipopolysaccharide and gingipains are also discussed.

Exploration of Potent Multi-Target-Directed-Ligands as Anti-Alzheimer’s Disease Agents: A Moiety Based Review

2021 ◽  
Vol 21 ◽  
Author(s):  
Pankaj Teli ◽  
Nusrat Sahiba ◽  
Jay Soni ◽  
Ayushi Sethiya ◽  
Dinesh Kumar Agarwal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disease ◽  
Cognitive Functions ◽  
Amyloid Β ◽  
Tau Hyperphosphorylation ◽  
Cinnamic Acids ◽  
Global Crisis ◽  
Acetylcholine Level

: Dementia is a chronic neurodegenerative disease and maximum of the cases are directly related to Alzheimer’s disease. More than 4 million people are living with Alzheimer’s disease related dementia in India, making it a global crisis. Alzheimer’s disease deteriorates cognitive functions with the passage of time and consists of multifaceted factors such as decline of acetylcholine level, amyloid β-aggregation, tau hyperphosphorylation, oxidative stress, etc. The classical drugs used till date, are focused on only one target and not serving the cause properly. Hence, the community of scientists are rigorously working on multi-target-directed agents that incorporate two or more active scaffolds in one compound or hybrid of active moieties. This article aims at the evaluation of novel potential compounds and moieties such as quinolines, chalcones, coumarins, chromenes, piperazine, carbazoles, cinnamic acids, tacrine hybrids, donepezil hybrids and so on that have been introduced as multi-target-directed agents in recent five years.

Tau Positive Neurons Show Marked Mitochondrial Loss and Nuclear Degradation in Alzheimer's Disease

2018 ◽  
Vol 15 (10) ◽  
pp. 928-937 ◽  
Author(s):  
Melissa Wee ◽  
Fariba Chegini ◽  
John H.T. Power ◽  
Shohreh Majd
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Marked Decrease ◽  
Neuronal Loss ◽  
Hyperphosphorylated Tau ◽  
Dystrophic Neurites ◽  
Mitochondrial Density ◽  
Amyloid Aβ ◽  
Nuclear Degradation ◽  
Tau Aggregation

Background: Alzheimer's disease (AD) pathology consists of intraneuronal neurofibrillary tangles, made of hyperphosphorylated tau and extracellular accumulation of beta amyloid (Aβ) in Aβ plaques. There is an extensive debate as to which pathology initiates and is responsible for cellular loss in AD. Methods: Using confocal and light microscopy, post mortem brains from control and AD cases, an antibody to SOD2 as a marker for mitochondria and an antibody to all forms of tau, we analyzed mitochondrial density in tau positive neurons along with nuclear degradation by calculating the raw integrative density. Results: Our findings showed an extensive staining of aggregated tau in cell bodies, dystrophic neurites and neurofilaments in AD with minimal staining in control tissue, along with a marked decrease in mitochondria in tau positive (tau+) neurons. The control or tau negative (tau-) neurons in AD contained an even distribution of mitochondria, which was greatly diminished in tau+ neurons by 40%. There were no significant differences between control and tau- neurons in AD. Tau+ neurons showed marked nuclear degradation which appeared to progress with the extent of tau aggregation. The aggregated tau infiltrated and appeared to break the nuclear envelope with progressively more DNA exiting the nucleus and associating with the aggregated intracellular tau. Conclusion: We report that the mitochondrial decrease is likely due to a decrease in the protein synthesis rather than a redistribution of mitochondria because of the decreased axonal transport. We suggest that the decrease in mitochondria and nuclear degradation are key mechanisms for the neuronal loss seen in AD.

scholarly journals Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mengyu Liu ◽  
Thomas Dexheimer ◽  
Dexin Sui ◽  
Stacy Hovde ◽  
Xiexiong Deng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prescription Drugs ◽  
Intracerebral Injection ◽  
Hyperphosphorylated Tau ◽  
Brain Correlates ◽  
Aggregation Inhibitors ◽  
Tau Aggregation ◽  
The Brain

Abstract The neurodegenerative Alzheimer’s disease (AD) affects more than 30 million people worldwide. There is thus far no cure or prevention for AD. Aggregation of hyperphosphorylated tau in the brain correlates with the cognitive decline of patients of AD and other neurodegenerative tauopathies. Intracerebral injection of tau aggregates isolated from tauopathy brains causes similar pathology in the recipient mice, demonstrating the pathogenic role of abnormally phosphorylated tau. Compounds controlling the aggregation of hyperphosphorylated tau therefore are probable modulators for the disease. Here we report the use of recombinant hyperphosphorylated tau (p-tau) to identify potential tauopathy therapeutics and risk factors. Hyperphosphorylation renders tau prone to aggregate and to impair cell viability. Taking advantage of these two characters of p-tau, we performed a screen of a 1280-compound library, and tested a selective group of prescription drugs in p-tau aggregation and cytotoxicity assays. R-(−)-apomorphine and raloxifene were found to be p-tau aggregation inhibitors that protected p-tau-treated cells. In contrast, a subset of benzodiazepines exacerbated p-tau cytotoxicity apparently via enhancing p-tau aggregation. R-(−)apomorphine and raloxifene have been shown to improve cognition in animals or in humans, whereas benzodiazepines were linked to increased risks of dementia. Our results demonstrate the feasibility and potential of using hyperphosphorylated tau-based assays for AD drug discovery and risk factor identification.

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