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

Seung Hoon Yang, Jisu Shin, Naewoo Neo Shin, Ji-Hyun Hwang, Sung-Chul Hong, Keunwan Park, Jae Wook Lee, Sejin Lee, Seungyeop Baek, Kyeonghwan Kim, Illhwan Cho, YoungSoo Kim

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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of toxic amyloid-β (Aβ) oligomers and plaques. Considering that Aβ misfolding and aggregation precedes the progressive development of cognitive impairment in AD, investigating a therapeutic means by clearance of pre-existing Aβ aggregates shows promise as a viable disease-modifying treatment. Here, we report that a small molecule, necrostatin-1 (Nec-1), reduces Aβ aggregates back to non-toxic monomers in vitro and in vivo. Intravenous administration of Nec-1 reduced the levels of Aβ plaques in the brains of aged APP/PS1 double transgenic mice. In addition, Nec-1 exhibited therapeutic effects against Aβ aggregates by inhibiting Aβ-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 Aβ. Given that the accumulation of Aβ 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.

Original languageEnglish
Pages (from-to)4183
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2019 Mar 12

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Yang, S. H., Shin, J., Shin, N. N., Hwang, J-H., Hong, S-C., Park, K., Lee, J. W., Lee, S., Baek, S., Kim, K., Cho, I., & Kim, Y. (2019). A small molecule Nec-1 directly induces amyloid clearance in the brains of aged APP/PS1 mice. Scientific reports, 9(1), 4183. https://doi.org/10.1038/s41598-019-40205-5