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

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

Author information

1
Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montreal, QC H1T 2M4, Canada.
2
Institute for Stem Cell Research and Regenerative Medicine, Faculty of Medicine Heinrich Heine University, Moorenstrasse 5 Building, 14.80 40225 Düsseldorf, Germany.
3
Research Center of the University of Montreal Hospital (CRCHUM), Montreal, QC H2X 0A9, Canada; Department of Neurosciences, University of Montreal, Montreal, QC Canada.
4
Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, 5415 Boul. l'Assomption, Montreal, QC H1T 2M4, Canada; Department of Neurosciences, University of Montreal, Montreal, QC Canada. Electronic address: gbernier.hmr@ssss.gouv.qc.ca.

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

PMID:
29847796
DOI:
10.1016/j.celrep.2018.04.097
[Indexed for MEDLINE]
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