A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer’s mouse model

Abstract

AbstractIntroductionTrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-β (Aβ)-toxicity. Upregulating TrkB/C signaling could reduce Alzheimer’s disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction.MethodsPTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APPL/S) and wild-type controls (WT). Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA-sequencing.ResultsMemory and LTP deficits in APPL/Smice were attenuated by treatment with BD10-2. BD10-2 prevented aberrant AKT, CaMKII, and GLUA1 phosphorylation, and enhanced activity-dependent recruitment of synaptic proteins. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription.ConclusionsBD10-2 prevented APPL/S/Aβ-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.