Rescue of synaptic pathology in an Alzheimer's mouse model by enhancing MET receptor tyrosine kinase signaling

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Project Summary/Abstract Alzheimer's disease (AD) imposes an overwhelming socioeconomic burden on our society. Key pathological hallmarks of the AD brain are degenerating cortical neurons with neurofibrillary tangles, Tau, and Aβ. At the cellular and functional level, AD is characterized by impaired synaptic function and synapse loss across many forebrain regions, and is manifested as disrupted synaptic plasticity, learning, memory, and general intellect. Mouse models recapitulating certain aspects of AD pathology have been extensively employed to study mechanisms of neural degeneration and assess efficacy of therapeutic interventions. Recent literature revealed that MET receptor tyrosine kinase, heavily expressed in the excitatory neurons at early developmental stages yet functions as a synaptic signaling protein in the adult brain, is reduced in AD brain. Activation of MET initiates a pleiotropic signaling that exerts neurotrophic and neuroprotective effects in multiple neurodegenerative mouse models. However, how MET signaling affects AD pathogenesis has not been investigated. The goal of this proposal is to test whether synaptic pathology in an AD mouse model can be rescued by enhanced MET-mediated signaling. Recent work from this research team showed that MET signaling in the developing cortical circuits promotes dendritic spine formation and synaptogenesis, refines circuit connectivity, and controls the timing of excitatory synapse maturation. More intriguingly, preliminary data using unique ‘humanized’ hMET conditional knockin (cKI) mice created in the PI’s laboratory revealed altered transcriptome profiles, increased hippocampal long term potentiation (LTP) and enhanced learning and memory. In addition, elevated MET signaling in adult hippocampal CA1 neurons resulted in enhanced synaptic transmission and increased spine density indicative of de novo synaptogenesis. These exciting results have led to the hypothesis that enhancing MET-mediated pleiotropic signaling prior to neurodegeneration in an amyloid AD mouse model (5xFAD) may rescue the disrupted molecular pathways, reduce pathological synapse losses, and alleviate the cognitive decline. To address this hypothesis, two specific aims are proposed to test whether hMET-cKI signaling alleviates molecular and pathological changes (Aim 1) and mitigates the synaptic loss and cognitive decline (Aim 2) in the 5xFAD mouse model. Impact: The hypothesized beneficial effects of hMET signaling highlight the potential of an endogenous pleiotropic developmental molecular signaling as a novel candidate for neurotrophic therapy in AD.