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

Research output: Contribution to journalArticle

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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Amyloid
Alzheimer Disease
Brain
Brain Death
Poisons
Therapeutic Uses
Neurodegenerative Diseases
Intravenous Administration
Computer Simulation
Transgenic Mice
Amines
necrostatin-1
Cell Death
Therapeutics
Cell Line

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Yang, Seung Hoon ; Shin, Jisu ; Shin, Naewoo Neo ; Hwang, Ji-Hyun ; Hong, Sung-Chul ; Park, Keunwan ; Lee, Jae Wook ; Lee, Sejin ; Baek, Seungyeop ; Kim, Kyeonghwan ; Cho, Illhwan ; Kim, YoungSoo. / A small molecule Nec-1 directly induces amyloid clearance in the brains of aged APP/PS1 mice. In: Scientific reports. 2019 ; Vol. 9, No. 1. pp. 4183.
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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.",
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Yang, SH, Shin, J, Shin, NN, Hwang, J-H, Hong, S-C, Park, K, Lee, JW, 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, vol. 9, no. 1, pp. 4183. https://doi.org/10.1038/s41598-019-40205-5

A small molecule Nec-1 directly induces amyloid clearance in the brains of aged APP/PS1 mice. / Yang, Seung Hoon; Shin, Jisu; Shin, Naewoo Neo; Hwang, Ji-Hyun; Hong, Sung-Chul; Park, Keunwan; Lee, Jae Wook; Lee, Sejin; Baek, Seungyeop; Kim, Kyeonghwan; Cho, Illhwan; Kim, YoungSoo.

In: Scientific reports, Vol. 9, No. 1, 12.03.2019, p. 4183.

Research output: Contribution to journalArticle

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DO - 10.1038/s41598-019-40205-5

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