Inhibition of SIRT2 promotes APP acetylation and ameliorates cognitive impairment in APP/PS1 transgenic mice

Aging is a primary risk factor for neurodegenerative diseases, such as Alzheimer’s disease (AD). SIRT2, an NAD+(nicotinamide adenine dinucleotide)-dependent deacetylase, accumulates in the aging brain. Here, we report that, in the amyloid precursor protein (APP)/PS1 transgenic mouse model of AD, genetic deletion of SIRT2 or pharmacological inhibition of SIRT2 ameliorates cognitive impairment. We find that suppression of SIRT2 enhances acetylation of APP, which promotes non-amyloidogenic processing of APP at the cell surface, leading to increased soluble APP-α (sAPPα). We discover that lysines 132 and 134 of the major pathogenic protein β-amyloid (Aβ) precursor are acetylated and that these residues are deacetylated by SIRT2. Strikingly, exogenous expression of wild-type or an acetylation-mimic APP mutant protects cultured primary neurons from Aβ42 challenge. Our study identifies SIRT2-mediated deacetylation of APP on K132 and K134 as a regulated post-translational modification (PTM) and suggests inhibition of SIRT2 as a potential therapeutic strategy for AD. [Display omitted] •SIRT2 interacts with and deacetylates the highly conserved N terminus of APP•SIRT2 inhibition promotes APP non-amyloidogenic processing at the cell surface•Acetylation of APP-K132/134 is neuroprotective in cultured hippocampal neurons•SIRT2 inhibition improves cognitive deficiency in Alzheimer’s disease mouse model Bai et al. show that SIRT2, a sirtuin deacetylase, interacts with the high-affinity ligand E1 domain of APP. Inhibition of SIRT2 has beneficial effects in APP/PS1 mice by maintaining acetylation of APP on the K132 and K134 residues, promoting production of neuroprotective sAPPα.