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Elucidating the role of the AD risk factor Pyk2 in tau‐induced neuronal dysfunction
Author(s) -
Brody Alex Harrison,
Strittmatter Stephen M.
Publication year - 2020
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 - 10.1002/alz.036625
Subject(s) - tauopathy , dentate gyrus , hippocampal formation , phosphorylation , neuroscience , phenotype , exacerbation , biology , hippocampus , quantitative trait locus , knockout mouse , psychology , disease , pathology , medicine , microbiology and biotechnology , genetics , immunology , neurodegeneration , gene
Background Genetic deletion of the AD risk factor Pyk2 exacerbates tau‐associated phenotypes in PS19 (MAPT P301S) animals, a well described mouse model for tauopathy. Method Aging studies and assessment of spatial memory impairment were conducted on PS19;Pyk2 knockout mice. Histological assessment of tau pathology and hippocampal cell layer thickness was also conducted. Pyk2's role in phosphorylating disease relevant residues of tau was assessed through pharmacological inhibition of Pyk2 in acute hippocampal slice preparations from PS19 animals. Result Genetic deletion of Pyk2 results in the exacerbation of early death phenotype and spatial memory impairment observed in PS19 animals. Genetic deletion of Pyk2 also results in the exacerbation of tau pathology as well as reduction in dentate gyrus cell layer thickness in PS19 animals. Pharmacological inhibition of Pyk2 results in an increase in tau phosphorylation (pTau S202/T205). Conclusion Pyk2 is protective against tau‐associated phenotypes in PS19 mice, and basal Pyk2 activity limits tau phosphorylation at disease relevant residues.