Abstract
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, Aβ40, and total and T181 phospho-Tau (pTau). AKAP9 mutations had no effect on Aβ40/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.
Highlights
We previously identified by whole exome sequencing two rare specific variants in A-kinase anchoring protein 9 (AKAP9) in a sample of African American (AA) Alzheimer disease (AD) cases and controls (Logue et al 2014)
Eleven AA subjects included in our previous study (Logue et al 2014) who had at least one of the AKAP9 mutations for rs144662445 and rs149979685 (AKAP9+) and available lymphoblastoid cell lines were identified in the MIRAGE Study cell repository at Boston University and at the National Cell Repository for Alzheimer Disease (NCRAD) at Indiana University
We examined the effect of AKAP9 mutations on the production of amyloid precursor protein (APP) and Aβ40 in lymphoblastoid cell lines (LCLs)
Summary
We previously identified by whole exome sequencing two rare specific variants in AKAP9 (rs144662445 and rs149979685) in a sample of African American (AA) Alzheimer disease (AD) cases and controls (Logue et al 2014). The odds of AD were increased 2.75-fold among individuals possessing one or both of these variants (AKAP9+). These SNPs were not present in more than 4000 sequenced individuals with European ancestry Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118, USA. Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA. 2010), suggesting that this variant is unique to persons of African ancestry. The functional characterization of AA-specific variants has not been studied
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