Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau.
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.
Li
Bin
B
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA.
Chohan
Muhammad Omar
MO
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001921:Brain / Q000648:ultrastructure; D003600:Cytosol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D016875:tau Proteins; D012694:Serine; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D015739:Nocodazole