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　(PrPC)　is　one　of　the　cell-surface　receptors　of　AβO　that　mediates　related　neurotoxicity.　Besides,　as　a　neuroprotective　protein,　the　dimerization　of　PrPCseems　to　be　critical　for　its　trophic　activity.　We　presume　that　modulating　PrPCreceptor　activity　could　be　another　potential　approach　to　abrogate　AβO　toxicity.　In　the　present　work,　using　an　aptamer-induced　dimerization　(AID)　strategy,　we　enforce　PrPCdimerization　and　modulate　its　neurotrophic　signaling.　The　AID　strategy　can　attenuate　AβO　toxic　action　by　(i)　interfering　with　AβO-PrPCinteraction　and　promoting　neuroprotective　shedding　of　PrPC(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　PrPCsignaling　may　shed　light　on　validating　new　therapeutic　strategies　in　AD.　©　2022　American　Chemical　Society.　All　rights　reserved.