Grant: Project Grant

Defining the fundamental mechanisms that underlie precise neuronal assembly during development and regeneration are critical not only for understanding all brain functions, but also for various developmental (e.g. Autism spectrum) and neurodegenerative disorders (e.g. Alzheimer's, Parkinson's etc.) that are met in clinical practice. Alzheimer's disease (AD) is one of the most common and debilitating neurodegenerative disorders globally, and the situation will only worsen with an aging population producing an unsustainable burden on our healthcare systems. Our understanding of the fundamental mechanisms underlying AD neuropathology remains however poor, and the treatment regimes are restricted to short-term symptom management at best. We have made a surprising finding implicating neurotrophic factors and the MEN1 tumor suppressor gene in the regulation of expression and synaptic maintenance of nicotinic acetylcholine receptors (nAChR), which regulate many aspects of learning and memory. A dramatic loss of cholinergic synaptic connections and transmission in the hippocampus is one of the most important neuropathological hallmarks of AD. Moreover, cholinergic synaptic activity is known to regulate the expression of neurotrophic factors (NTF) and their reduced expression in hippocampus is commonly observed in AD. Using mouse models and human brain tissue, we will test a novel hypothesis that a deficit in neurotrophic factor-dependent expression of MEN1 underlies nAChR dysfunction in AD. We will seek to determine how MEN1 gene function underlies the regulation of nAChR expression during NTF-dependent synapse formation and synaptic plasticity, and whether its perturbation generates cognitive and neuropathological hallmarks of AD. We anticipate that our novel and exciting findings will lead to transformative insights into synaptic mechanisms of AD - at a resolution never achieved before, and identify new pathways as putative targets for therapeutic intervention.