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.
Citations
Mar 4, 2020·International Journal of Molecular Sciences·Xiaozeng LinDamu Tang
Mar 15, 2020·Journal of Neuroscience Research·Gary X D'SouzaJessica E Young
Jan 27, 2019·Scientific Reports·Jida El HajjarGilbert Bernier
Jan 15, 2020·NPJ Precision Oncology·Anthony FlamierGilbert Bernier
Jul 28, 2020·Genes·Ryan HoganGilbert Bernier
Jun 30, 2019·International Forum of Allergy & Rhinology·Rhea ChoiBradley J Goldstein
Jul 8, 2020·International Journal of Molecular Sciences·Soraia MartinsJames Adjaye
Apr 9, 2019·Open Biology·Yi-Ying WuHung-Chih Kuo
Dec 9, 2020·Experimental Gerontology·Elena E TzekakiΑnastasia A Pantazaki
Feb 9, 2021·Reviews in the Neurosciences·Asiamah Ernest AmponsahHuixian Cui
Mar 2, 2021·Neural Regeneration Research·Eleonora NardiniGilbert Bernier
Jan 6, 2021·NPJ Precision Oncology·Anthony FlamierGilbert Bernier
Mar 25, 2021·Nature Communications·Roy HannaGilbert Bernier
Nov 7, 2020·Neuropharmacology·Anup K SrivastavaSurajit Karmakar
Jan 1, 2019·Epigenomes·Janise N Kuehner, Bing Yao
Oct 7, 2021·Alzheimer's Research & Therapy·Jun Pyo KimUNKNOWN Alzheimer’s Disease Neuroimaging Initiative
Oct 10, 2021·FEBS Letters·Camille Ravel-GodreuilJulia Fuchs