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

Latif-Hernandez, A.; Yang, T.; Raymond-Butler, R.; Moran-Losada, P.; Minhas, P.; White, H.; Tran, K. C.; Liu, H.; Simmons, D.; Langness, V.; Andreasson, K.; Wyss-Coray, T.; Longo, F. M.

doi:10.1101/2023.09.18.558138

bioRxiv · 10.1101/2023.09.18.558138

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

Latif-Hernandez, A.·Yang, T.·Raymond-Butler, R.·Moran-Losada, P.·Minhas, P.·White, H.·Tran, K. C.·Liu, H.·Simmons, D.·Langness, V.·Andreasson, K.·Wyss-Coray, T.·Longo, F. M.

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Abstract

IntroductionTrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-{beta} (A{beta})-toxicity. Upregulating TrkB/C signaling could reduce Alzheimers 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/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. ConclusionsBD10-2 prevented APPL/S/A{beta}-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.

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Latif-Hernandez, A., Yang, T., Raymond-Butler, R., Moran-Losada, P., Minhas, P., White, H., Tran, K. C., Liu, H., Simmons, D., Langness, V., Andreasson, K., Wyss-Coray, T., Longo, F. M.. 2023-09-20. 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. https://doi.org/10.1101/2023.09.18.558138

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