A small molecule Nec-1 directly induces amyloid clearance in the brains of aged APP/PS1 mice

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of toxic amyloid-beta (A beta) oligomers and plaques. Considering that A beta misfolding and aggregation precedes the progressive development of cognitive impairment in AD, investigating a therapeutic means by clearance of pre-existing A beta aggregates shows promise as a viable disease-modifying treatment. Here, we report that a small molecule, necrostatin-1 (Nec-1), reduces A beta aggregates back to non-toxic monomers in vitro and in vivo. Intravenous administration of Nec-1 reduced the levels of A beta plaques in the brains of aged APP/ PS1 double transgenic mice. In addition, Nec-1 exhibited therapeutic effects against A beta aggregates by inhibiting A beta-induced brain cell death in neuronal and microglial cell lines. Nec-1 also showed anti-apoptotic and anti-necroptotic effects in the cortex of aged APP/ PS1 mice by reducing levels of phosphorylated-RIPK3 and Bax and increasing the levels of Bcl-2. According to our data in vitro and in silico, the methyl group of the amine in the 2-thioxo-4-imidazolidinone is the key moiety of Nec-1 that directs its activity against aggregated A beta. Given that the accumulation of A beta aggregates is an important hallmark of AD, our studies provide strong evidence that Nec-1 may serve a key role in the development of AD treatment.