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 INTRODUCTION Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, and synaptic dysfunction. METHODS PTX‐BD10‐2 (BD10‐2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APP L/S ) and wild‐type controls. Effects on memory and hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing. RESULTS In APP L/S mice, BD10‐2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium‐calmodulin–dependent kinase II (CaMKII), and AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10‐2 also had potentially favorable effects on LTP‐dependent complement pathway and synaptic gene transcription. DISCUSSION BD10‐2 prevented APP L/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. Highlights Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long‐term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model. Modulation of TrkB and TrkC regulates synaptic activity‐dependent transcription. TrkB and TrkC receptors are candidate targets for translational therapeutics. Electrophysiology combined with transcriptomics elucidates synaptic restoration. LTP identifies neuron and microglia AD‐relevant human‐mouse co‐expression modules.