A TrkB and TrkC partial agonist prevents synaptic plasticity deficits and elicits activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's disease mouse model

Introduction: TrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-ß (Aß)-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 (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. Results: Memory and LTP deficits in APPL/S mice 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. Conclusions: BD10-2 prevented APPL/S/Aß-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. Overall design: To investigate transcriptional changes associated with LTP and BD10-2 treatment in the context of an amyloid model (Thy1-hAPPLond/Swe [Line 41] mice) of Alzheimer's, we conducted RNA sequencing on eight experimental groups. All mice were either Wildtype (B6) or T41B mice, dosed via oral gavage with BD10-2 or vehicle for 3 months from 13-16 months of age. Afterwards, right hippocampal slices were rapidly dissected for ephysiology (stimulated or unstimulated control), subjected to 3 times theta burst stimulation consisting of 10 bursts of 4 stimuli at 100 Hz separated by 200 ms each. Unstimulated slices experienced sham procedure of the same duration without TBS. Immediately after slices were flash frozen for RNAseq processing.