Project 460557

Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting tens of millions of people worldwide, characterized by a gradual loss of memory and other cognitive functions. Two misfolded proteins are of particular importance in the study of AD; amyloid-beta which form the characteristic plaques, and phosphorylated-tau (p-tau) which accumulates inside neurons to form neurofibrillary tangles. There are indications that inflammation and immune cell activation, including microglia, play an important role in the development of the pathology in AD. Current studies within our research group suggests that Amyloid-beta plaque load can increase activated microglia, but these alone do not correlate with behavioural deficits. I propose that the interaction between the misfolded Amyloid and p-tau plus the brain's immune response cause neuronal loss and impairments associated with AD. An effective AD pathology mouse model with both mutant human amyloid and human tau is needed. Non-overexpressing transgenic AD mouse models generating both human amyloid and tau will be injected (seeded) with p-tau homogenate from AD patient or control, to understand the role and spreading mechanisms of p-tau. Treatments investigated will be a decrease in activated microglia or a model of acute infection. Assessment of memory and cognitive function, using behavioral tasks, will be combined with measurements of Amyloid-beta, p-tau and inflammation markers using fluorescent labels and molecular techniques, to evaluate the importance of inflammation and microglia on memory impairments and histological markers associated with AD. The proposed research project will increase the scientific understanding of the interaction between Amyloid-beta, p-tau and inflammation in AD and age-related dementia. Insights in the relationship between brain pathology and behavioral manifestations of the disease will improve the selection of targets for intervention.