P53-dependent SIRT6 expression protects A?42-induced DNA damage.

ABSTRACT: Alzheimer's disease (AD) is the most common type of dementia and age-related neurodegenerative disease. Elucidating the cellular changes that occur during ageing is an important step towards understanding the pathogenesis and progression of neurodegenerative disorders. SIRT6 is a member of the mammalian sirtuin family of anti-aging genes. However, the relationship between SIRT6 and AD has not yet been elucidated. Here, we report that SIRT6 protein expression levels are reduced in the brains of both the 5XFAD AD mouse model and AD patients. A?42, a major component of senile plaques, decreases SIRT6 expression, and A?42-induced DNA damage is prevented by the overexpression of SIRT6 in HT22 mouse hippocampal neurons. Also, there is a strong negative correlation between A?42-induced DNA damage and p53 levels, a protein involved in DNA repair and apoptosis. In addition, upregulation of p53 protein by Nutlin-3 prevents SIRT6 reduction and DNA damage induced by A?42. Taken together, this study reveals that p53-dependent SIRT6 expression protects cells from A?42-induced DNA damage, making SIRT6 a promising new therapeutic target for the treatment of AD.

SUBMITTER: Jung ES 

PROVIDER: S-EPMC4860716 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature