Dataset Information

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

SUBMITTER: Yang SH

PROVIDER: S-EPMC6414664 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Yang Seung-Hoon SH Shin Jisu J Shin Naewoo Neo NN Hwang Ji-Hyun JH Hong Sung-Chul SC Park Keunwan K Lee Jae Wook JW Lee Sejin S Baek Seungyeop S Kim Kyeonghwan K Cho Illhwan I Kim YoungSoo Y

Scientific reports 20190312 1

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 mono ...[more]

PMID: 30862818

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Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.

Dataset Information

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

Publications

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

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