Project Summary/AbstractAlzheimer's disease (AD) imposes an overwhelming socioeconomic burden on our society. Key pathologicalhallmarks of the AD brain are degenerating cortical neurons with neurofibrillary tangles Tau and A. At thecellular and functional level AD is characterized by impaired synaptic function and synapse loss across manyforebrain 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 studymechanisms of neural degeneration and assess efficacy of therapeutic interventions. Recent literaturerevealed that MET receptor tyrosine kinase heavily expressed in the excitatory neurons at earlydevelopmental 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 inmultiple neurodegenerative mouse models. However how MET signaling affects AD pathogenesis has notbeen investigated. The goal of this proposal is to test whether synaptic pathology in an AD mouse model canbe rescued by enhanced MET-mediated signaling. Recent work from this research team showed that METsignaling in the developing cortical circuits promotes dendritic spine formation and synaptogenesis refinescircuit connectivity and controls the timing of excitatory synapse maturation. More intriguingly preliminarydata using unique humanized hMET conditional knockin (cKI) mice created in the PIs laboratory revealedaltered transcriptome profiles increased hippocampal long term potentiation (LTP) and enhanced learning andmemory. In addition elevated MET signaling in adult hippocampal CA1 neurons resulted in enhanced synaptictransmission and increased spine density indicative of de novo synaptogenesis. These exciting results haveled to the hypothesis that enhancing MET-mediated pleiotropic signaling prior to neurodegeneration in anamyloid AD mouse model (5xFAD) may rescue the disrupted molecular pathways reduce pathologicalsynapse losses and alleviate the cognitive decline. To address this hypothesis two specific aims areproposed to test whether hMET-cKI signaling alleviates molecular and pathological changes (Aim 1) andmitigates the synaptic loss and cognitive decline (Aim 2) in the 5xFAD mouse model. Impact: Thehypothesized beneficial effects of hMET signaling highlight the potential of an endogenous pleiotropicdevelopmental molecular signaling as a novel candidate for neurotrophic therapy in AD.