Modeling Late-Onset Sporadic Alzheimer's Disease through BMI1 Deficiency

Cell Rep. 2018 May 29;23(9):2653-2666. doi: 10.1016/j.celrep.2018.04.097.

Abstract

Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1. BMI1 knockout in human post-mitotic neurons resulted in amyloid beta peptide secretion and deposition, p-Tau accumulation, and neurodegeneration. Mechanistically, BMI1 was required to repress microtubule associated protein tau (MAPT) transcription and prevent GSK3beta and p53 stabilization, which otherwise resulted in neurodegeneration. Restoration of BMI1 activity through genetic or pharmaceutical approaches could represent a therapeutic strategy against AD.

Keywords: Alzheimer’s disease; BMI1; GSK3b; MAPT; Tau; amyloid; dementia; p53; polycomb; sporadic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Dementia / metabolism
  • Dementia / pathology
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Models, Biological*
  • Neurons / metabolism
  • Phosphorylation
  • Polycomb Repressive Complex 1 / deficiency*
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • tau Proteins / metabolism

Substances

  • Amyloid
  • BMI1 protein, human
  • Tumor Suppressor Protein p53
  • tau Proteins
  • Polycomb Repressive Complex 1
  • Glycogen Synthase Kinase 3 beta

Grant support