Peptide aptamer targeting Aβ–PrP–Fyn axis reduces Alzheimer’s disease pathologies in 5XFAD transgenic mouse model

Currently, no effective therapeutics exist for the treatment of incurable neurodegenerative diseases such as Alzheimer’s disease (AD). The cellular prion protein (PrP(C)) acts as a high-affinity receptor for amyloid beta oligomers (AβO), a main neurotoxic species mediating AD pathology. The interaction of AβO with PrP(C) subsequently activates Fyn tyrosine kinase and neuroinflammation. Herein, we used our previously developed peptide aptamer 8 (PA8) binding to PrP(C) as a therapeutic to target the AβO–PrP–Fyn axis and prevent its associated pathologies. Our in vitro results indicated that PA8 prevents the binding of AβO with PrP(C) and reduces AβO-induced neurotoxicity in mouse neuroblastoma N2a cells and primary hippocampal neurons. Next, we performed in vivo experiments using the transgenic 5XFAD mouse model of AD. The 5XFAD mice were treated with PA8 and its scaffold protein thioredoxin A (Trx) at a 14.4 µg/day dosage for 12 weeks by intraventricular infusion through Alzet(®) osmotic pumps. We observed that treatment with PA8 improves learning and memory functions of 5XFAD mice as compared to Trx-treated 5XFAD mice. We found that PA8 treatment significantly reduces AβO levels and Aβ plaques in the brain tissue of 5XFAD mice. Interestingly, PA8 significantly reduces AβO–PrP interaction and its downstream signaling such as phosphorylation of Fyn kinase, reactive gliosis as well as apoptotic neurodegeneration in the 5XFAD mice compared to Trx-treated 5XFAD mice. Collectively, our results demonstrate that treatment with PA8 targeting the AβO–PrP–Fyn axis is a promising and novel approach to prevent and treat AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04785-w.