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.
Highlights
We performed silver staining of SDS-PAGE with photo-induced cross-linking of unmodified proteins (PICUP) to visualize and compare the quantitative bands of Aβ species when treated with Nec-1
We examined the effects of Nec-1 on pre-existing Aβ plaques using aged APPswe/PS1-dE9 double-transgenic mouse models (APP/PS1)
Such Aβ-disaggregating ability of Nec-1 protects neuronal and microglial cell death induced by Aβ aggregates
Summary
Following studies showed evidences that necroptosis are associated with neuronal cell death in multiple neurodegenerative diseases and Nec-1 inhibit such degeneration in cellular and animal models of several brain disorders[22,23,24,25]. When administered to adult APP/PS1 mice in a preventive manner before formation of protein aggregates and cognitive impairment, Nec-1 inhibited the development of Aβ and tau abnormalities[26]. We investigated the effects of Nec-1 on pre-existing Aβ aggregates in vitro, in vivo, and in silico. Afterwards, we examined the progressive effects of Nec-1 on Aβ aggregates-induced cell death of neuronal and microglial cell lines. To further assess therapeutic ability of Nec-1 for mouse study, Nec-1 was administered to amyloid-rich aged APP/PS1 mice by intravenous injection and changes in the levels of Aβ plaques were examined
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