Grant: Project Grant

Alzheimer's disease is the most common form of dementia in the elderly. As the world's population ages, many advanced countries including Canada face a growing burden of care for patients with Alzheimer's disease. Loss of brain cell connections called synapses is an early pathological feature of Alzheimer's disease and is strongly correlated with cognitive impairment. A protein called amyloid-beta that is deposited in plaques in the brains of patients with Alzheimer's disease can induce synapse loss and dysfunction. Our project aims to reveal how to prevent amyloid-beta-induced synapse pathology by uncovering mechanisms through which amyloid-beta leads to synapse loss and dysfunction. We have recently discovered that amyloid-beta oligomers interact with and disrupt the function of synaptic cell adhesion molecules called neurexins. Neurexins play essential roles in synapse formation and plasticity as well as in cognitive functions such as learning and memory. We also identified neurexin-binding proteins that may be able to protect neurexins from amyloid-beta-mediated disruption. Using comprehensive advanced techniques in cellular biology, biochemistry and electrophysiology as well as ultrastructural imaging and behavioural experiments, we will determine how neurexins and their binding partners influence amyloid-beta-induced synapse pathology and also determine whether and how inhibition of amyloid-beta-neurexin interaction rescues the synaptic and cognitive deficits of Alzheimer's disease model mice. In summary, our proposed study is crucial to elucidate mechanisms underlying synapse pathology and cognitive impairment in Alzheimer's disease, which could facilitate translational medicine and drug discovery to alleviate synapse loss and dysfunction for cognitive improvement in Alzheimer's disease.