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O4‐04‐04: Hyperphosphorylation Determines Both the Spread and the Morphology of Tau Pathology
Author(s) -
Hu Wen,
Zhang Xinhua,
Xie Shutao,
Tung Yunn Chyn,
Liu Fei,
Iqbal Khalid
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.627
Subject(s) - hyperphosphorylation , tau protein , tauopathy , tau pathology , hippocampus , pathology , hippocampal formation , immunostaining , protein phosphatase 2 , phosphatase , dephosphorylation , chemistry , phosphorylation , biology , neuroscience , alzheimer's disease , neurodegeneration , immunohistochemistry , medicine , microbiology and biotechnology , disease
Background: Neurofibrillary pathology of abnormally hyperphosphorylated tau (P-tau) is a hallmark of Alzheimer’s disease (AD) and other tauopathies. Tau pathology can be experimentally induced and propagated. However, what induces the prion-like transmission-character to tau and produces morphologically distinct tau lesions remains elusive. We sought to investigate the role of hyperphosphorylation in the spread of tau pathology in hTau transgenic mice. Methods:We first isolated oligomeric, hyperphosphorylated tau from AD brain (AD P-tau) using an established protocol by us previously, and dephosphorylated AD P-tau in vitro with protein phosphatase 2A (PP2A). We then injected AD P-tau or PP2A-treated AD P-tau, using recombinant Tau441 and saline as controls, bilaterally into hippocampi (0.12 mg tau each) of 3 month-old hTau mice which express all six isoforms of wildtype human tau, and characterized the induced tau pathology by immunostaining for phospho-tau and Thioflavin-S staining at 6, 9 and 11 months post-injection. Results:We found that intra-hippocampal injection with AD P-tau, but not non-phosphorylated tau or saline, produced numerous P-tau tangles and neuropil threads both locally and in cerebral cortex lateral to injection site and upstream to the hippocampus. Dephosphorylation of AD P-tau with protein phosphatase-2A dramatically reduced (by w75%) and switched tau pathology from tangles to argyrophilic grainlike morphology. Conclusions: Abnormal hyperphosphorylation of tau determines the spread and the morphology of tau lesions and the propagation of tau pathology takes place both locally and in axonally connected areas, highlighting tau hyperphosphorylation as a potential therapeutic target.