Project 458981

Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting tens of millions of people worldwide and characterized by a gradual loss of memory and other cognitive functions. Two misfolded proteins, amyloid (Aß) and phosphorylated-tau (p-tau), are of particular interest in the study of AD. Aß fragments accumulate in the extracellular matrix to form characteristic plaques and p-tau deposits accumulated inside cells to form neurofibrillary tangles (NFTs). There are indications that inflammation and immune cells including microglia play an important role in the development of the pathology in AD. Fundamental research using animal models is very useful to understand the factors and mechanisms involved in disease processes. Interestingly, Aß plaque loads don't seem correlated with behavioural deficits. We hypothesise that the level of p-tau or inflammation could be better indicators of behavioral deficits or progression of the disease and, that p-tau pathology is influenced by systemic inflammation. New labeling compounds and imaging techniques are now available to evaluate the presence and time course of p-tau and Aß in in vivo imaging and for whole brain imaging and reconstruction. We are proposing to modify the systemic inflammation level using pharmacological agents. P-tau will be seeded in susceptible animal models. We will combine behavioural evaluation of memory and cognitive functions using behavioural tasks with in vivo imaging and post-mortem measurements of Aß, p-tau and inflammation markers using fluorescent labels and molecular techniques in mouse models of AD. This proposed research project would increase scientific understanding of role of Aß, p-tau and inflammation and the mechanisms controlling their presence and spread in AD and age-related dementia. This would lead to a better understanding of the relationship between brain pathology and behavioural manifestations of the disease and guide the selection of future intervention targets.