Open AccessTau Phosphorylation is Impacted by Rare AKAP9 Mutations Associated with Alzheimer Disease in African Americans
Author(s) -
Tsuneya Ikezu,
Ci-Di Chen,
Annina M. DeLeo,
Ella Zeldich,
M. Daniele Fallin,
Nicholas M. Kanaan,
Kathryn L. Lunetta,
Carmela R. Abraham,
Mark W. Logue,
Lindsay A. Farrer
Publication year - 2018
Publication title -
journal of neuroimmune pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.219
H-Index - 70
eISSN - 1557-1904
pISSN - 1557-1890
DOI - 10.1007/s11481-018-9781-x
Subject(s) - mutation , microbiology and biotechnology , biology , kinase , phosphorylation , protein kinase a , rolipram , tau protein , gene , amyloid precursor protein , alzheimer's disease , phosphodiesterase , genetics , biochemistry , medicine , disease , enzyme
We studied the effect of two rare mutations (rs144662445 and rs149979685) in the A-kinase anchoring protein 9 (AKAP9) gene, previously associated with Alzheimer disease (AD) in African Americans (AA), on post-translational modifications of AD-related pathogenic molecules, amyloid precursor protein (APP) and microtubule-associated protein Tau using lymphoblastoid cell lines (LCLs) from 11 AA subjects with at least one AKAP9 mutation and 17 AA subjects lacking these mutations. LCLs were transduced by viral vectors expressing causative AD mutations in APP or human full-length wild type Tau. Cell lysates were analyzed for total APP, Aβ 40 , and total and T181 phospho-Tau (pTau). AKAP9 mutations had no effect on Aβ 40 /APP, but significantly increased pTau/Tau ratio in LCLs treated with phosphodiesterase-4 inhibitor rolipram, which activates protein kinase A. Proteomic analysis of Tau interactome revealed enrichment of RNA binding proteins and decrease of proteasomal molecules in rolipram-treated cells with AKAP9 mutations. This study shows the impact of rare functional AKAP9 mutations on Tau, a central mechanism of AD pathogenesis, in LCLs derived from AD and control subjects.