Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau
TLDR
This study provides direct mechanistic insights into the molecular basis of both axonal and dendritic neurodegeneration seen in Alzheimer disease by following the effects of hyperphosphorylated tau on microtubule dynamics in real time.Abstract:
Hyperphosphorylated tau has long been proposed as the key molecule disrupting normal neuronal microtubule dynamics and leading to neurofibrillary degeneration in Alzheimer disease. Here we provide a direct evidence of hyperphosphorylated tau-induced disruption of microtubule network. Using Nocodozole-treated and detergent-extracted cells, we created a neuronal environment in mouse embryonic fibroblasts, 3T3 cells, by replacing their cytoplasm with adult rat brain cytosol. By recreating neuronal microtubule network in these cells, we were able to follow the effects of hyperphosphorylated tau on microtubule dynamics in real time. Whereas recombinant human brain tau promoted assembly and bundling of microtubules, abnormally hyperphosphorylated tau isolated from Alzheimer disease brain cytosol (AD P-tau) inhibited the assembly and disrupted preformed microtubule network by sequestering normal brain tau and MAP2. This breakdown of the microtubule network was reversed by treatment of the extracted cells with protein phosphatase-2A. This study, for the first time, provides direct mechanistic insights into the molecular basis of both axonal and dendritic neurodegeneration seen in Alzheimer disease.read more
Citations
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Mechanisms of tau-induced neurodegeneration
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References
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Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology
Inge Grundke-Iqbal,Khalid Iqbal,Yunn-Chyn Tung,Maureen Quinlan,Henryk M. Wisniewski,Lester I. Binder +5 more
TL;DR: It is suggested that tau in Alzheimer brain is an abnormally phosphorylated protein component of PHF, the two major locations of paired-helical filaments in Alzheimer disease brain.
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A protein factor essential for microtubule assembly
TL;DR: The unique ability of tau to restore the normal features of in vitro microtubules assembly makes it likely that tau is a major regulator of microtubule formation in cells.
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Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.
TL;DR: Human brain tau and paired helical filament polypeptides co-migrated on sodium dodecyl sulfate-polyacrylamide gels suggest that tau is a major component of Alzheimer paired helicals filaments.
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Tau pathology in Alzheimer disease and other tauopathies
Khalid Iqbal,Alejandra del C. Alonso,She Chen,M. Omar Chohan,Ezzat El-Akkad,Cheng-Xin Gong,Sabiha Khatoon,Bin Li,Fei Liu,Abdur Rahman,Hitoshi Tanimukai,Inge Grundke-Iqbal +11 more
TL;DR: Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.
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Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments
TL;DR: It appears that τ self-assembles by association of the microtubule binding domains/repeats and that the abnormal hyperphosphorylation promotes the self-assembly of τ into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.