Peptides alleviate cognitive impairment by inhibiting and disassembling amyloid-beta aggregates in Alzheimer disease

Gao, W.; Gao, B.; Wang, S.; Wu, D.; Mei, P.; Geng, L.; Li, C.; Li, Y.; Liu, X.; Pan, J.; Huang, J.; Deng, Y.; Chen, X.; saiyin, H.; Yu, H.; Li, S.; Zhang, Q.; Xu, B.; Huang, F.; Ming, C.; Wu, H.; Li, J.

doi:10.1101/2025.05.28.656730

bioRxiv · 10.1101/2025.05.28.656730

Peptides alleviate cognitive impairment by inhibiting and disassembling amyloid-beta aggregates in Alzheimer disease

Gao, W.·Gao, B.·Wang, S.·Wu, D.·Mei, P.·Geng, L.·Li, C.·Li, Y.·Liu, X.·Pan, J.·Huang, J.·Deng, Y.·Chen, X.·saiyin, H.·Yu, H.·Li, S.·Zhang, Q.·Xu, B.·Huang, F.·Ming, C.·Wu, H.·Li, J.

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Abstract

Alzheimers disease (AD) is a devasting neurodegenerative disorder characterized by {beta}-amyloid formation, further exacerbated by RIPK1/RIPK3 necrosome-induced programmed necrosis (necroptosis). We previously showed that the RIPK1/RIPK3 necrosome forms a functional amyloid complex using its RIP homotypic interaction motifs (RHIMs). Here, we discovered that the core RIPK1/RIPK3 necrosome shares strikingly structural similarity to the C-terminal region of {beta}-amyloid (A{beta}42), and the RHIM-derived tetrapeptides (IQIG or VQVG) directly inhibit A{beta} aggregation, disassemble preformed A{beta} fibrils (PFFs), and reduce RIPK1 polymerization. Also, the peptides exhibit effective membrane permeability and could reduce A{beta}40 or A{beta}42-induced neural death and TNF-induced necroptosis in SH-SY5Y cells. IQIG and VQVG injected by ICV increase learning and memory abilities by reducing A{beta} plaques and hyperphosphorylated tau in the cortex and hippocampus of APP/PS1 double-transgenic mice. Mechanistically, the peptides directly interact with A{beta} to block A{beta} aggregation and alleviate microglia-mediated neuroinflammation. Strikingly, single-cell RNA sequencing revealed that the peptides-treated AD transgenic mice restored neuronal homeostasis with increased GABAergic neurons and decreased glutamatergic neurons. Furthermore, total cell-cell interaction strength increased while the AD risk gene Apoe expression decreased in the specific oligodendrocyte subtype of peptides-treated AD mice. Thus, our findings revealed that the peptides could improve cognition and memory capabilities and serve as promising structural templates for potential drugs against AD.

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Gao, W., Gao, B., Wang, S., Wu, D., Mei, P., Geng, L., Li, C., Li, Y., Liu, X., Pan, J., Huang, J., Deng, Y., Chen, X., saiyin, H., Yu, H., Li, S., Zhang, Q., Xu, B., Huang, F., Ming, C., Wu, H., Li, J.. 2025-06-01. Peptides alleviate cognitive impairment by inhibiting and disassembling amyloid-beta aggregates in Alzheimer disease. https://doi.org/10.1101/2025.05.28.656730

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