The Role of beta-catenin Stabilization in the Synaptic Pathology of Alzheimer’s Disease

Alzheimer's disease (AD) is a devastating neurological disorder characterized by the loss of cognitive function and an inability to process and store new memories, caused by the progressive death of neurons (brain cells). It is becoming increasingly evident that before neurons die, changes can be observed at their synapses – the junction between neurons across which information is transmitted. Deficits in synaptic function, loss of synapses, and a reduced ability to form new synapses are the major correlates of dementia. 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, play a critical role in regulating the formation and remodelling of synapses. Both molecules also associate with presenilin-1 (PS1), a protein that normally degrades (breaks down) b-catenin. Mutations in the PS1 gene account for nearly 70 per cent of early-onset familial AD cases. Fergil Mills is investigating the effects on neurons when b-catenin is not normally degraded by PS1. Using isolated neurons and a mouse model, he is characterizing the synaptic consequences of stabilizing (maintaining) b-catenin in neurons, and determining the molecular mechanisms of b-catenin in the development of synaptic structures. These studies will help determine whether b-catenin stabilization leads to the synaptic pathology and cognitive deficits seen in AD. Mills’ studies will further our understanding of synapse pathology and cognitive deficits, and could lead to new treatments for patients with AD or other neurological disorders.