Peptides alleviatecognitive impairment by inhibiting and disassembling amyloid-β aggregates in Alzheimer’s disease

ABSTRACT: Alzheimer’s disease (AD) is a devasting neurodegenerative disorder characterized by β-amyloid formation, which is 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 β-amyloid, and the RIPK1/RIPK3 RHIM tetrapeptides (IQIG or VQVG) directly inhibit Aβ aggregation, disassemble preformed Aβ fibrils (PFFs), and reduce RIPK1 polymerization in vitro. In cells, the IQIG and VQVG tetrapeptides reduce Aβ-induced neural death and TNFα-induced necroptosis, suggesting that they may inhibit Aβ toxicity via both a direct effect on Aβ aggregation and an indirect effect on interfering with necroptosis. In vivo, IQIG and VQVG increase learning and memory abilities by reducing Aβ plaques and hyperphosphorylated tau in the cortex and hippocampus of APP/PS1 double-transgenic mice. Mechanistically, the peptides directly interact with Aβ to block Aβ aggregation and alleviate microglia-mediated neuroinflammation. Strikingly, single-cell RNA sequencing revealed that the peptides restored neuronal homeostasis in the hippocampus of treated mice, supporting their therapeutic mechanisms. Thus, our findings revealed that the peptides could improve cognition and memory capabilities and serve as promising structural templates for potential drugs against AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE242308 | GEO | 2026/09/05

REPOSITORIES: GEO