scholarly journals CHIP-mediated hyperubiquitylation of tau promotes its self-assembly into the insoluble tau filaments

2021 ◽  
Author(s):  
Ji Hyeon Kim ◽  
Jeeyoung Lee ◽  
Won Hoon Choi ◽  
Seoyoung Park ◽  
Seo Hyeong Park ◽  
...  
Keyword(s):  
Self Assembly ◽  
Tau Phosphorylation ◽  
Key Driver ◽  
Multiple Hit ◽  
Tau Aggregation

Multiple-hit model for tau aggregation, where sequential events of tau phosphorylation and hyperubiquitylation function as a key driver of the fibrillization process.

scholarly journals “Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yuxing Xia ◽  
Stefan Prokop ◽  
Benoit I. Giasson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Kinase Inhibitors ◽  
Tau Phosphorylation ◽  
Phosphorylated Tau ◽  
Clinical Biomarkers ◽  
Early Results ◽  
Recent Developments ◽  
Tau Aggregation

AbstractPhosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau  could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

scholarly journals Living supramolecular polymerization of fluorinated cyclohexanes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Oleksandr Shyshov ◽  
Shyamkumar Vadakket Haridas ◽  
Luca Pesce ◽  
Haoyuan Qi ◽  
Andrea Gardin ◽  
...  
Keyword(s):  
Dipole Moment ◽  
Self Assembly ◽  
Materials Science ◽  
Helical Structure ◽  
The Self ◽  
Supramolecular Polymers ◽  
Aliphatic Compound ◽  
Double Helical Structure ◽  
Key Driver ◽  
Supramolecular Polymerization

AbstractThe development of powerful methods for living covalent polymerization has been a key driver of progress in organic materials science. While there have been remarkable reports on living supramolecular polymerization recently, the scope of monomers is still narrow and a simple solution to the problem is elusive. Here we report a minimalistic molecular platform for living supramolecular polymerization that is based on the unique structure of all-cis 1,2,3,4,5,6-hexafluorocyclohexane, the most polar aliphatic compound reported to date. We use this large dipole moment (6.2 Debye) not only to thermodynamically drive the self-assembly of supramolecular polymers, but also to generate kinetically trapped monomeric states. Upon addition of well-defined seeds, we observed that the dormant monomers engage in a kinetically controlled supramolecular polymerization. The obtained nanofibers have an unusual double helical structure and their length can be controlled by the ratio between seeds and monomers. The successful preparation of supramolecular block copolymers demonstrates the versatility of the approach.

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 Tau Phosphorylation, Aggregation, and Cell Toxicity

2006 ◽  
Vol 2006 ◽  
pp. 1-5 ◽  
Author(s):  
J. Avila ◽  
I. Santa-María ◽  
M. Pérez ◽  
F. Hernández ◽  
F. Moreno
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disorders ◽  
Protein Aggregates ◽  
Tau Phosphorylation ◽  
Cell Toxicity ◽  
Tau Aggregation

Protein aggregation takes place in many neurodegenerative disorders. However, there is a controversy about the possible toxicity of these protein aggregates. In this review, this controversy is discussed, focussing on the tau aggregation that takes place in those disorders known as tauopathies.

Tau cleavage and tau aggregation in neurodegenerative disease

2010 ◽  
Vol 38 (4) ◽  
pp. 1016-1020 ◽  
Author(s):  
Diane P. Hanger ◽  
Selina Wray
Keyword(s):  
Neurodegenerative Disease ◽  
Conformational Changes ◽  
Tau Phosphorylation ◽  
Cell Models ◽  
Tau Pathology ◽  
Binding Domains ◽  
Pathological Conditions ◽  
Tau Aggregation ◽  
The Brain ◽  
Tau Cleavage

Deposition of highly phosphorylated tau in the brain is the most significant neuropathological and biochemical characteristic of the group of neurodegenerative disorders termed the tauopathies. The discovery of tau fragments in these diseases suggests that tau cleavage and tau phosphorylation, both of which induce conformational changes in tau, could each have roles in disease pathogenesis. The identities of the proteases responsible for degrading tau, resulting in the appearance of truncated tau species in physiological and pathological conditions, are not known. Several fragments of tau are reported to have pro-aggregation properties, but the lack of disease-relevant cell models of tau aggregation has hampered investigation of the effects of tau aggregation on normal cellular functioning. In the present paper, we describe our findings of N-terminally truncated tau in the brain in a subgroup of the tauopathies in which tau isoforms containing four microtubule-binding domains predominate. We also discuss the evidence for the involvement of proteases in the generation of tau pathology in neurodegenerative disease, since these enzymes warrant further investigation as potential therapeutic targets in the tauopathies.

scholarly journals Neuroprotective Studies of Evodiamine in an Okadaic Acid-Induced Neurotoxicity

2021 ◽  
Vol 22 (10) ◽  
pp. 5347
Author(s):  
Ching-Hsuan Chou ◽  
Chia-Ron Yang
Keyword(s):  
Western Blotting ◽  
Okadaic Acid ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Neuroprotective Effect ◽  
Brain Slices ◽  
Neuronal Cell ◽  
Tau Phosphorylation ◽  
Mitogen Activated Protein Kinase ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease, and it manifests as progressive memory loss and cognitive decline. However, there are no effective therapies for AD, which is an urgent problem to solve. Evodiamine, one of the main bioactive ingredients of Evodia rutaecarpa, has been reported to ameliorate blood–brain barrier (BBB) permeability and improve cognitive impairment in ischemia and AD mouse models. However, whether evodiamine alleviates tauopathy remains unclear. This study aimed to examine whether evodiamine ameliorates tau phosphorylation and cognitive deficits in AD models. Methods: A protein phosphatase 2A inhibitor, okadaic acid (OA), was used to induce tau phosphorylation to mimic AD-like models in neuronal cells. Protein expression and cell apoptosis were detected using Western blotting and flow cytometry, respectively. Spatial memory/cognition was assessed using water maze, passive avoidance tests, and magnetic resonance imaging assay in OA-induced mice models, and brain slices were evaluated further by immunohistochemistry. Results: The results showed that evodiamine significantly reduced the expression of phosphor-tau, and further decreased tau aggregation and neuronal cell death in response to OA treatment. This inhibition was found to be via the inhibition of glycogen synthase kinase 3β, cyclin-dependent kinase 5, and mitogen-activated protein kinase pathways. In vivo results indicated that evodiamine treatment ameliorated learning and memory impairments in mice, whereas Western blotting and immunohistochemical analysis of the mouse brain also confirmed the neuroprotective effects of evodiamine. Conclusions: Evodiamine can decrease the neurotoxicity of tau aggregation and exhibit a neuroprotective effect. Our results demonstrate that evodiamine has a therapeutic potential for AD treatment.

scholarly journals Loss of presenilin function enhances tau phosphorylation and aggregation in mice

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Carlos M. Soto-Faguás ◽  
Paula Sanchez-Molina ◽  
Carlos A. Saura
Keyword(s):  
Inflammatory Responses ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Memory Deficits ◽  
Brain Regions ◽  
Tau Phosphorylation ◽  
Conditional Knockout ◽  
Synaptic Proteins ◽  
Genes Encoding ◽  
Tau Aggregation

AbstractMutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer’s disease (AD). Although the mechanisms by which these mutations affect Aβ are well defined, the precise role PS/γ-secretase on tau pathology in neurodegeneration independently of Aβ is largely unclear. Here we report that neuronal PS deficiency in conditional knockout (cKO) mice results in age-dependent brain atrophy, inflammatory responses and accumulation of pathological tau in neurons and glial cells. Interestingly, genetic inactivation of presenilin 1 (PS1) or both PS genes in mutant human Tau transgenic mice exacerbates memory deficits by accelerating phosphorylation and aggregation of tau in excitatory neurons of vulnerable AD brain regions (e.g., hippocampus, cortex and amygdala). Remarkably, neurofilament (NF) light chain (NF-L) and phosphorylated NF are abnormally accumulated in the brain of Tau mice lacking PS. Synchrotron infrared microspectroscopy revealed aggregated and oligomeric β-sheet structures in amyloid plaque-free PS-deficient Tau mice. Hippocampal-dependent memory deficits are associated with synaptic tau accumulation and reduction of pre- and post-synaptic proteins in Tau mice. Thus, partial loss of PS/γ-secretase in neurons results in temporal- and spatial-dependent tau aggregation associated with memory deficits and neurodegeneration. Our findings show that tau phosphorylation and aggregation are key pathological processes that may underlie neurodegeneration caused by familial AD-linked PSEN mutations.

scholarly journals Long-Term Overexpression of Heme Oxygenase 1 Promotes Tau Aggregation in Mouse Brain by Inducing Tau Phosphorylation

2011 ◽  
Vol 26 (2) ◽  
pp. 299-313 ◽  
Author(s):  
Yang Hui ◽  
Dayong Wang ◽  
Wenjing Li ◽  
Lina Zhang ◽  
Jianfeng Jin ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Heme Oxygenase ◽  
Tau Phosphorylation ◽  
Heme Oxygenase 1 ◽  
Tau Aggregation

scholarly journals Antisense Oligonucleotide-Mediated Reduction of HDAC6 Does Not Reduce Tau Pathology in P301S Tau Transgenic Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonio Valencia ◽  
Veronica L. Reinhart Bieber ◽  
Bekim Bajrami ◽  
Galina Marsh ◽  
Stefan Hamann ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Antisense Oligonucleotide ◽  
Tau Phosphorylation ◽  
Histone Deacetylase 6 ◽  
Tau Pathology ◽  
Tau Aggregation ◽  
The Brain ◽  
Mediated Reduction ◽  
Tau Acetylation

Acetylation of tau protein is dysregulated in Alzheimer's Disease (AD). It has been proposed that acetylation of specific sites in the KXGS motif of tau can regulate phosphorylation of nearby residues and reduce the propensity of tau to aggregate. Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme involved in deacetylation of multiple targets, including tau, and it has been suggested that inhibition of HDAC6 would increase tau acetylation at the KXGS motifs and thus may present a viable therapeutic approach to treat AD. To directly test the contribution of HDAC6 to tau pathology, we intracerebroventricularly injected an antisense oligonucleotide (ASO) directed against HDAC6 mRNA into brains of P301S tau mice (PS19 model), which resulted in a 70% knockdown of HDAC6 protein in the brain. Despite a robust decrease in levels of HDAC6, no increase in tau acetylation was observed. Additionally, no change of tau phosphorylation or tau aggregation was detected upon the knockdown of HDAC6. We conclude that HDAC6 does not impact tau pathology in PS19 mice.

scholarly journals Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

2022 ◽  
Author(s):  
Alexa Pichet Binette ◽  
Nicolai Franzmeier ◽  
Nicola Spotorno ◽  
Michael Ewers ◽  
Matthias Brendel ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Early Stage ◽  
Accumulation Rate ◽  
Amyloid Β ◽  
Therapeutic Approaches ◽  
Main Driver ◽  
Key Driver ◽  
Soluble P ◽  
Aβ Fibrils ◽  
Tau Aggregation

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. In early stages of AD, increased concentration of soluble CSF p-tau was the main driver of accumulation of insoluble tau aggregates across the brain, and mediated the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations were mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations were associated with cognitive decline, which was mediated by faster increase of tau aggregates. In AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline was driven by the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.

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