| First Author | Yang SH | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 4183 |
| PubMed ID | 30862818 | Mgi Jnum | J:275878 |
| Mgi Id | MGI:6307176 | Doi | 10.1038/s41598-019-40205-5 |
| Citation | Yang SH, et al. (2019) A small molecule Nec-1 directly induces amyloid clearance in the brains of aged APP/PS1 mice. Sci Rep 9(1):4183 |
| abstractText | Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of toxic amyloid-beta (Abeta) oligomers and plaques. Considering that Abeta misfolding and aggregation precedes the progressive development of cognitive impairment in AD, investigating a therapeutic means by clearance of pre-existing Abeta aggregates shows promise as a viable disease-modifying treatment. Here, we report that a small molecule, necrostatin-1 (Nec-1), reduces Abeta aggregates back to non-toxic monomers in vitro and in vivo. Intravenous administration of Nec-1 reduced the levels of Abeta plaques in the brains of aged APP/PS1 double transgenic mice. In addition, Nec-1 exhibited therapeutic effects against Abeta aggregates by inhibiting Abeta-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 Abeta. Given that the accumulation of Abeta 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. |
