Affiliation:
1. Department of Neurology & Neurological Sciences Stanford University School of Medicine Palo Alto California USA
2. Wu Tsai Neurosciences Institute, Stanford University Stanford California USA
3. Chan Zuckerberg Biohub San Francisco California USA
4. The Phil and Penny Knight Initiative for Brain Resilience Stanford University Stanford California USA
Abstract
AbstractINTRODUCTIONTropomyosin 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.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. Effects on memory and hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing.RESULTSIn APPL/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.DISCUSSIONBD10‐2 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.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.
Funder
National Institutes of Health
Arizona Department of Health Services
Arizona Biomedical Research Commission
Jean Perkins Foundation
Applebaum Foundation
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