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

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.