p53-dependent SIRT6 expression protects Aβ42-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. Aβ42, a major component of senile plaques, decreases SIRT6 expression, and Aβ42-induced DNA damage is prevented by the overexpression of SIRT6 in HT22 mouse hippocampal neurons. Also, there is a strong negative correlation between Aβ42-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 Aβ42. Taken together, this study reveals that p53-dependent SIRT6 expression protects cells from Aβ42-induced DNA damage, making SIRT6 a promising new therapeutic target for the treatment of AD.

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“…Interestingly, research also shows that p53-dependent SIRT6 expression could protect against Aβ42-induced DNA damage [71]. Aβ 42 decreases SIRT6 and p53 levels, which is related to the JNK signaling pathway [71]. Overexpression of SIRT6 is shown to prevent Aβ42-induced DNA damage, and the SIRT6 activators could serve as a novel therapeutic target for AD and cancers.…”

“…It has been shown that SIRT6 expression is decreased in the brains of patients with Alzheimer's disease. Interestingly, research also shows that p53-dependent SIRT6 expression could protect against Aβ42-induced DNA damage [71]. Aβ 42 decreases SIRT6 and p53 levels, which is related to the JNK signaling pathway [71].…”

“…This suggests that KDM3A might be a potential therapeutic agent for human breast cancer, as well as a prevention strategy. We have established that a good understanding of the actual mechanisms and the particular proteins involved in DNA repair is required to develop therapeutic approaches for cancer and some neurodegenerative disorders such as Alzheimer's disease (AD) (the most common type of dementia and age-related neurodegenerative disease) [71]. It has been shown that SIRT6 expression is decreased in the brains of patients with Alzheimer's disease.…”

“…In many cancer forms, p53 is mutated, leading to severe malignancy. Of all genes in human cancer, p53 has been identified as the most frequently (50%) mutated [70,71,73]. p53 accumulates during DNA damage resulting in cell death, necessitating the regulation of p53 via multiple pathways.…”

“…Aggressive cancer development and changes in gene activity exclusive of changes in DNA sequence (epigenetic) are linked to mutant p53 protein, which has implications for such difficult-to-treat cancers as those in the pancreas and breast [66]. p53 is highly respected as the cellular security of the genome, most especially because it protects cells from physiological stress by piloting the expression of genes that put into effect some of the vital cellular processes such as cycle arrest, apoptosis, and DNA repair and modifications ( Figure 3) [70][71][72]. p53 is an important tumour suppressor protein that kills cancer/tumour cells via apoptosis and aging.…”