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

• DOI: 10.1002/alz.13857
• Publication Date: 2024-05-23T08:41:24Z
• Authors: Amira Latif‐Herna...; Tao Yang; Robert R. Butler; Patricia Moran Lo...; Paras S. Minhas; Halle White; Kevin C. Tran; Harry Liu; Danielle A. Simmons; Vanessa Langness; Katrin I. Andreasson; Tony Wyss‐Coray; Frank M. Longo
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health; Research Article

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