Aptamer-Induced-Dimerization Strategy Attenuates AβO Toxicity through Modulating the Trophic Activity of PrP C Signaling.

Current therapeutic strategies for Alzheimer's disease (AD) mainly focus on amyloid β oligomer (AβO) formation or clearance. However, most of them have failed to yield good clinical results. There is an urgent need to explore an alternative therapeutic target for AD treatments. Recent studies have indicated that the cellular prion protein (PrP C ) is one of the cell-surface receptors of AβO that mediates related neurotoxicity. Besides, as a neuroprotective protein, the dimerization of PrP C seems to be critical for its trophic activity. We presume that modulating PrP C receptor activity could be another potential approach to abrogate AβO toxicity. In the present work, using an aptamer-induced dimerization (AID) strategy, we enforce PrP C dimerization and modulate its neurotrophic signaling. The AID strategy can attenuate AβO toxic action by (i) interfering with AβO-PrP C interaction and promoting neuroprotective shedding of PrP C ; (ii) preventing the AβO-induced mitochondrial dysfunction and the caspase-3-induced apoptosis; and (iii) reducing the secretion of inflammatory cytokines and relieving the neuroinflammation microenvironment. Our findings suggest that the strategy targeting PrP C signaling may shed light on validating new therapeutic strategies in AD.