ANK1 is up-regulated in laser captured microglia in Alzheimer's brain; the importance of addressing cellular heterogeneity

PLoS One. 2017 Jul 12;12(7):e0177814. doi: 10.1371/journal.pone.0177814. eCollection 2017.

Abstract

Recent epigenetic association studies have identified a new gene, ANK1, in the pathogenesis of Alzheimer's disease (AD). Although strong associations were observed, brain homogenates were used to generate the data, introducing complications because of the range of cell types analyzed. In order to address the issue of cellular heterogeneity in homogenate samples we isolated microglial, astrocytes and neurons by laser capture microdissection from CA1 of hippocampus in the same individuals with a clinical and pathological diagnosis of AD and matched control cases. Using this unique RNAseq data set, we show that in the hippocampus, ANK1 is significantly (p<0.0001) up-regulated 4-fold in AD microglia, but not in neurons or astrocytes from the same individuals. These data provide evidence that microglia are the source of ANK1 differential expression previously identified in homogenate samples in AD.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Ankyrins / genetics*
  • Ankyrins / metabolism
  • Case-Control Studies
  • Female
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Male
  • Microglia / metabolism*
  • Neurons / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Up-Regulation*

Substances

  • ANK1 protein, human
  • Ankyrins
  • RNA, Messenger

Grant support

This work was supported by New Investigator Research Grant-Alzheimer’s Association NIRG-15-321390 and Arizona Department of Health Services ADHS16-104646 FY2015-16 to D.M. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.