Grant: Team Grant: China-Canada: Alzheimer's Disease and Related Disorders

The accumulation of Abeta peptides in the form of neurotoxic soluble aggregates is a key molecular and neuropathological feature of Alzheimer's disease (AD). Changes in synaptic plasticity mediated by the neurotoxic effects of these soluble oligomeric assemblies of Abeta are thought to underlie at least some of the early cognitive impairments associated with AD. Although hypothesis-driven experiments have produced several leads, the underlying mechanisms remain controversial. Recently, we undertook hypothesis-free genome-wide association studies (GWAS) in search of new genes causally associated with AD. This genetic screen identified two kinase genes (EPHA1 and PTK2B) that are strongly associated with AD (p<10E-10), and that are likely to be involved in the synaptic injury in AD. In addition, we have recently demonstrated that a third kinase, protein kinase D (PKD1) plays a previously unrecognised, but important role in synaptic plasticity. The present proposal will examine how these kinases (and their respective signalling pathways) are involved in Abeta-mediated synaptic toxicity. The proposed programme builds upon: i) substantial preliminary data generated in our labs in China and Canada; and ii) on the unique skills present in each lab. These are critical features which make the program FULLY FEASIBLE. The program will provide KNOWLEDGE EXCHANGE AND TRAINING by supporting graduate student, postdoctoral and staff scientist exchanges to labs with different skill sets. This program will provide a BETTER UNDERSTANDING OF THE DISEASE MECHANISMS. This knowledge will be an essential cornerstone for future TRANSLATIONAL use in the development of BIOMARKERS (that measure activation of these mechanisms and thus disease presence/ activity) and NOVEL THERAPIES (that block these mechanisms). Kinases are highly tractable targets for both SMALL MOLECULE and BIOLOGICAL THERAPIES including those from TRADITIONAL CHINESE MEDICINE.