1. Heterochromatic genome instability and neurodegeneration sharing similarities with Alzheimer’s disease in old Bmi1+/− mice
- Author
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Gilbert Bernier, Patrick Nkanza, Yiu Chung Tse, Tak Pan Wong, Wassim Chatoo, Mohamed Abdouh, Nicolas Tétreault, Roy Hanna, and Jida El Hajjar
- Subjects
Male ,0301 basic medicine ,Genome instability ,Amyloid ,Heterochromatin ,DNA damage ,Transgene ,Long-Term Potentiation ,lcsh:Medicine ,Mice, Transgenic ,tau Proteins ,Kaplan-Meier Estimate ,macromolecular substances ,Biology ,Genomic Instability ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Gene silencing ,Maze Learning ,lcsh:Science ,Spatial Memory ,Neurons ,Polycomb Repressive Complex 1 ,Amyloid beta-Peptides ,Multidisciplinary ,lcsh:R ,Neurodegeneration ,Brain ,medicine.disease ,Chromatin ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Female ,lcsh:Q ,030217 neurology & neurosurgery - Abstract
Sporadic Alzheimer’s disease (AD) is the most common cause of dementia. However, representative experimental models of AD have remained difficult to produce because of the disease’s uncertain origin. The Polycomb group protein BMI1 regulates chromatin compaction and gene silencing. BMI1 expression is abundant in adult brain neurons but down-regulated in AD brains. We show here that mice lacking one allele of Bmi1 (Bmi1+/−) develop normally but present with age cognitive deficits and neurodegeneration sharing similarities with AD. Bmi1+/− mice also transgenic for the amyloid beta precursor protein died prematurely and present aggravated disease. Loss of heterochromatin and DNA damage response (DDR) at repetitive DNA sequences were predominant in Bmi1+/− mouse neurons and inhibition of the DDR mitigated the amyloid and Tau phenotype. Heterochromatin anomalies and DDR at repetitive DNA sequences were also found in AD brains. Aging Bmi1+/− mice may thus represent an interesting model to identify and study novel pathogenic mechanisms related to AD.
- Published
- 2019
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