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[P4–094]: TARGETING TAU AGGREGATION IN BRAIN SLICE CULTURE MODELS OF TAUOPATHIES
Author(s) -
Croft Cara L.,
Cruz Pedro E.,
Goodwin Marshall S.,
CeballosDiaz Carolina,
Strang Kevin,
Chakrabarty Paramita,
Levites Yona,
Giasson Benoit I.,
Golde Todd E.
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.2017.06.1959
Subject(s) - tauopathy , microglia , neuroscience , ex vivo , biology , in vivo , tau protein , transduction (biophysics) , cellular model , in vitro , cell culture , disease , alzheimer's disease , microbiology and biotechnology , medicine , pathology , neurodegeneration , immunology , inflammation , genetics , biochemistry
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.