Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Alzheimer's disease (AD) is a devastating neurological disorder characterized by the loss of cognitive function and an inability to encode new memories. Mounting evidence suggests that disruption of synapse formation and function is the major correlate of AD symptoms, and temporally precedes out-and-out neuronal loss. It is therefore crucial to understand the basic biology of synapses, and how these processes are affected in AD. The cadherin family of cell adhesion molecules and their intracellular partner, b-catenin, is of utmost interest in AD research. The cadherin/b-catenin complex plays a critical role in regulating the formation and remodelling of synapses, and both molecules associate with presenilin-1 (PS1), a protein which targets b-catenin for degradation. Nearly 70% of early-onset familial AD cases are accounted for by mutations in the PS1 gene, most of which disrupt PS1's role in b-catenin degradation and lead the accumulation of b-catenin. We hypothesize that increased b-catenin levels contribute significantly to synaptic pathology observed in AD cases caused by mutations in the PS1 gene, and predict that stabilization of b-catenin levels will disrupt synapse plasticity due to aberrant cadherin-based adhesion. We will use transgenic mice with conditionally stabilized b-catenin and increased intracellular b-catenin levels, and test our hypothesis through examinations of hippocampal neuron cultures and tests of learning and memory. We predict the increase in b-catenin levels will mimic the synaptic pathology observed in AD, will allow us to assess the impact of synapse pathology on neuronal function and behaviour, and will provide a mouse model for AD - a critical component for preclinical testing of novel disease treatments. This study will further our understanding of synapse pathology and cognitive deficits, and could lead to new treatments for patients with AD or other neurological disorders.