Aims

Alzheimer’s disease (AD) is a complex multifactorial disease in which neural death occurs predominantly by apoptosis. The p53 protein functions as a key regulator of apoptosis and accumulates in brains from AD patients. This protein naturally occurs in humans in two functional polymorphic variants, resulting in Arg or Pro at residue 72, which regulates p53 apoptotic activity. Here we evaluate the relevance of the p53 Arg72Pro single nucleotide polymorphism (SNP) in Amyloid-β(Aβ)-induced neurotoxicity both in vitro and in vivo.

Methods

We used primary cortical neurons from humanized Tp53 Arg72Pro knock-in mice treated with Aβ oligomers (10 µM) and an Aβ (5 nmol) intracerebroventricular injection model in Tp53 Arg72Pro knock-in mice to assess mitochondrial function, neurodegeneration and cognitive status.

Results

We found that the Arg genotype increased neuronal susceptibility to Aβ toxicity upon p53 mitochondrial stabilization in vitro. Accordingly, Arg72 mice were more susceptible to Aβ-induced neurodegeneration and memory loss than Pro72 mice. Interestingly, treatment with PFTμ (40 mgKg^-1), a small molecule that inhibits p53 mitochondrial binding without affecting its transactivation activity, prevented Aβ-induced memory deficit in Arg72 mice.

Conclusions

Our results demonstrate that blocking the p53-mitochondria interaction prevents cognitive decline in Aβ-injected mice. Moreover, PFTμ may be useful to develop novel therapeutic approaches for AD, especially in patients carrying the Arg72 SNP variant.

Funded by Instituto de Salud Carlos III (PI18/00265; RD16/0019/0018); FEDER; European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement 686009) and Junta de Castilla y León (Escalera de Excelencia (CLU-2017-03 Cofinanciado por el P.O. FEDER de Castilla y León).