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DT‐02‐05: Dephosphorylation both diminishes and alters the spread of Alzheimer tau‐induced pathology in mice
Author(s) -
Hu Wen,
Zhang Xinhua,
Xie Shutao,
Tung Yunn Chyn,
Liu Fei,
Iqbal Khalid
Publication year - 2015
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.2015.08.161
Subject(s) - tau pathology , hyperphosphorylation , phosphatase , dephosphorylation , hippocampus , protein phosphatase 2 , genetically modified mouse , tau protein , pathology , chemistry , knockout mouse , endocrinology , medicine , alzheimer's disease , biology , microbiology and biotechnology , phosphorylation , transgene , biochemistry , disease , receptor , gene
Background: Tau pathology can be induced and propagated by intracerebral injection with tau seeds from affected brain. However, what makes tau transmissible producing neurofibrillary pathology remains unclear. Our previous studies showed that Alzheimer’s disease (AD) abnormally hyperphosphorylated tau (AD P-tau) sequesters normal tau to form bundles of filaments in a non-saturatable fashion, and the sequestration is abolished by treating AD P-tau with alkaline phosphatase in vitro (Alonso et al., Nat Med 2: 783, 1996) . In this study, we tested the role of hyperphosphorylation on spread of tau pathology in a transgenic mouse model, in which murine tau is replaced with genomic human tau. Methods:AD P-tau, prepared from affected AD cerebral cortex using the protocol established by us previously, was dephosphorylated with protein phosphatase 2A (PP2A), the main tau phosphatase. PP2A could dephosphorylate tau at S198/199/ 202 and S262/356 but ineffectively at S396/404. Either untreated or PP2A-treated AD P-tau, 0.12 mg in a total volume of 2.5 ml in saline, was injected bilaterally into the hippocampus of 3 months old hTau-Tg mice, which express all six isoforms of nonmutated human tau. The same amount of tau441 or saline alone were injected as controls. Homozygous murine tau knockout mice (tau), the genotype control for hTau-Tg mice, were injected with either AD P-tau or saline as another set of controls. Results: At 9 months after injection, mice were sacrificed for immunohistochemistry. Numerous AT8 (pS202/pT205) positive neurons, with overt neuropil threads and tangle-like appearance, were seen in the hippocampus and overlaying cortex in mice injected with AD P-tau, but neither in tau nor in tau441 and saline groups. In PP2A-treated AD P-tau group the number of stained neurons with tauopathy was dramatically reduced and argyrophilic grains and neuropil threads were observed. The brains which showed AT8 immunoreactivity were also immunopositive with anti-tau 6-18 mAb (43D); tau recipient mice did not show any immunoreactivity. Conclusions: These findings suggest that the propagation of tau pathology is most likely hyperphosphorylation dependent both in density and morphology of the lesions and involves via sequestration of endogenous tau by seeded hyperphosphorylated tau. (Supported by NYS Office of People with Developmental Disabilities.)