Heterochromatic genome instability and neurodegeneration sharing similarities with Alzheimer\u2019s disease in old Bmi1+/\u2212 mice

Jida El Hajjar,Patrick Nkanza,Roy Hanna,Nicolas Tétreault,Tak Pan Wong,Yiu Chung Tse,Wassim Chatoo,Gilbert Bernier,Mohamed Abdouh

doi:10.1038/s41598-018-37444-3

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.

Highlights

Alzheimer’s disease of the late-onset sporadic form (AD) is the most common dementia[1]
We previously reported that Bmi1+/− mice have reduced median and maximal lifespan along with apparition of lens cataracts at higher frequencies than WT littermates, suggesting that Bmi[1] hemi-deficiency may accelerate the aging process[18]
Values are mean ± SEM. *P < 0.05; (**) < 0.01; Student’s t-test. (d) Immunoblot using extracts from the frontal cortex of age-match control and AD patients. (d’) Quantification of the results showed in (d). (e) Immunoblot using extracts from the hippocampus of age-match control and Familial AD (FAD) patients. (f) IHC staining for p-Ataxia Telengectasia Mutated (ATM) on paraffin sections from the frontal cortex of age-match control (n = 2) and AD (n = 2) patients. phospho-ATM at Serine 1981 (p-ATM) is predominant in AD neurons and accumulates in both cytosolic and nuclear compartments. (g) Chromatin Immunoprecipitaion (ChIP) experiments were performed on frontal cortex extracts of age-match control (n = 6) and AD brains (n = 6)

Summary

Introduction

Alzheimer’s disease of the late-onset sporadic form (AD) is the most common dementia[1]. Carriers of the apolipoprotein E4 (APOE4) allele have a higher risk to develop the disease with age[2]. Familial AD (FAD) is an early-onset, autosomal dominant disorder, that is associated with mutations in amyloid beta precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and representing less than 5% of all Alzheimer’s disease cases[3]. Bmi1-deficiency in mice is associated with accumulation of DNA damage www.nature.com/scientificreports/. We show that mice lacking one Bmi[1] allele (Bmi1+/−) develop normally, but display with age a pathology sharing some similarities with AD. Loss of heterochromatin and DDR at repetitive DNA sequences in neurons was characteristic of Bmi1+/− mice and AD brains. Loss of one Bmi[1] allele in mice predisposes to age-related neurodegeneration sharing some similarities with AD

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Conclusion