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[P4–093]: SITE‐SPECIFIC PHOSPHORYLATION OF TAU INHIBITS AMYLOID‐β TOXICITY IN ALZHEIMER's MICE
Author(s) -
Ittner Arne
Publication year - 2017
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.2017.06.1958
Subject(s) - phosphorylation , p38 mitogen activated protein kinases , neuroscience , postsynaptic potential , cyclin dependent kinase 5 , neurodegeneration , kinase , toxicity , tau protein , microbiology and biotechnology , protein kinase a , biology , alzheimer's disease , chemistry , medicine , biochemistry , disease , receptor , mitogen activated protein kinase kinase
Background:Amyloid-b (Ab) toxicity in Alzheimer’s disease (AD) is considered to be mediated by phosphorylated tau protein. Methods:Our study used mouse genetics, adeno-associated virus-mediated gene delivery, primary neuronal culture, biochemical, imaging and histological techniques as well as telemetric electroencephalography and behavioural tests including standard memory testing and touch screen operant chambers. Results: In contrast to previous assumptions on tau phosphorylation, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Ab toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38g and interfered with postsynaptic excitotoxic signaling complexes engaged by Ab. Accordingly, depletion of p38g exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mouse model of AD, whereas increasing the activity of p38g abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Abinduced neuronal death and offered protection from excitotoxicity. Conclusions: Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.