Bridging integrator 1 (BIN1) in oligodendrocyte connects myelin degradations to age-related dementia

Abstract

Alzheimer's disease (AD) is one of the most prevalent age-related diseases all over the world. Although the gene mutations responsible for familial AD (fAD) have been identified, the mechanism for sporadic AD (sAD) remains elusive. Drugs based on the traditional amyloid cascade hypothesis have faced continuous failures in clinical trials and alternative hypotheses regarding DNA damage, neuronal cell cycle re-entry, Bridging Integrator 1 (BIN1) was identified to be the second strongest genetic risk factor for sAD in a genome-wide association study. Its association with oligodendrocytes (OLs), DNA damage, and ataxia telangiectasia mutated (ATM) – a DNA repair gene- may play a significant role in the development of AD. We proposed that myelin degradation is attributed to the DNA damage in mature OLs, which may be involved in the AD pathogenesis. In addition, we hypothesized that BIN1 is the bridging molecule between DNA damage repair (DDR) and cell cycle control in OLs, in which a specific Bin1 isoform may contribute to this function. In this study, we confirmed that the expression of BIN1 decreases in correlation with myelin loss in human AD and MS samples. The reduction of BIN1 expression was in line with the severity of the Braak stage. We found that BIN1 was predominantly expressed in WM rather than GM. These findings were recapitulated in mouse models with cuprizone (CPZ) - induced demyelination. We showed that Bin1, especially Bin1 isoform 1 and 2, were upregulated upon CPZ treatment. Additionally, it was revealed that Bin1 level was observed in the OLs and was reduced in the genu after the CPZ treatment. To determine the correlation between Atm and Bin1, two distinct Atm-KO mouse models were used, and showed that loss of Atm leads to the decline of the whole population of mature OLs. In addition, the primary OL progenitor cells (OPC) also showed Bin1 upregulation when exposed to DNA damage by etoposide treatment. Our study so far supports our hypothesis that BIN1 may play a role in AD pathogenesis, especially in terms of myelin abnormality.