Tau Phosphorylation is Impacted by Rare AKAP9 Mutations Associated with Alzheimer Disease in African Americans

J Neuroimmune Pharmacol. 2018 Jun;13(2):254-264. doi: 10.1007/s11481-018-9781-x. Epub 2018 Mar 7.

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.

Keywords: AKAP9; APP; African American; Alzheimer disease; Amyloid-β peptide; Rolipram; Tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / genetics*
  • African Americans
  • Aged
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Cytoskeletal Proteins / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Mutation, Missense
  • Phosphorylation
  • Protein Processing, Post-Translational / genetics*
  • tau Proteins / metabolism*

Substances

  • A Kinase Anchor Proteins
  • AKAP9 protein, human
  • Cytoskeletal Proteins
  • MAPT protein, human
  • tau Proteins