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.

Autor: Latif-Hernandez A; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., Yang T; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., Butler RR 3rd; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., Losada PM; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California, USA., Minhas PS; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., White H; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., Tran KC; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., Liu H; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., Simmons DA; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., Langness V; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA., Andreasson KI; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California, USA.; Chan Zuckerberg Biohub, San Francisco, California, USA., Wyss-Coray T; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California, USA.; The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, California, USA., Longo FM; Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California, USA.
Jazyk: angličtina
Zdroj: Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2024 Jul; Vol. 20 (7), pp. 4434-4460. Date of Electronic Publication: 2024 May 23.
DOI: 10.1002/alz.13857
Abstrakt: 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.
(© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
Databáze: MEDLINE
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