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

Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Anthony Flamier, Jida El Hajjar, James Adjaye, Karl J. Fernandes, Mohamed Abdouh, Gilbert Bernier
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.

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Teaser

Flamier et al. report on a role of BMI1 in sporadic Alzheimer's disease (AD) pathogenesis. They show reduced BMI1 expression in AD brains and cortical neurons compared to non-demented controls, familial AD, frontotemporal dementia, and Lewy body dementia. Human neurons deficient for BMI1 display pathological hallmarks of AD. Their work suggests that BMI1 reduction results in AD pathology through de-repression of MAPT and stabilization of GSK3beta and p53.


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