Grant: Discovery Horizons

Over 7.5 hundred thousand Canadians are living with dementia, according to the Alzheimer’s Association, and the Public Health Agency of Canada reported that dementia cost Canadians $8.3 billion dollars in 2011, and if this trend continues, the figure may double by 2031. Making up the dominant majority of causes leading to dementia, Alzheimer’s disease belongs to a group of neurodegenerative diseases known as tauopathies characterized by the aggregation and spreading of misfolded tau protein, which remains latent for many years until clinical symptoms like memory loss appear when a considerable portion of neurons in the brain are severely affected or permanently damaged. Hence, developing a computational method to accurately predict the spatiotemporal evolution of tau pathology can be a game changer in the fight against dementia, which is the main focus of this proposal. Due to the availability of in vitro measurement techniques, a major portion of previous computational methods are confined to in vitro, where high concentrations of free tau in the presence of an anionic aggregation inducer are used to support and accelerate aggregation, while our premier aim is to understand what happens in the brain, where tau monomers and aggregates with various concentrations are inextricably interacted and simultaneously affected by other pathways, such as protein turnover and clearance process, in an inhomogeneous and anisotropic medium. Although several computational models have been developed for in vivo tau pathology, none of them takes into account the simultaneous impacts of directionality and nonlinearity on the transmission of toxic tau species to the best of our knowledge. In addition, Aβ oligomers and tau exacerbate glutamate production and inhibit its recapture. Thus, brain hyperactivation is that it reflects glutamatergic excitotoxicity. As part of our methodology for realistically modeling such complex simultaneous impacts, there is a need to conduct animal experiments including immunohistochemistry with AT8 antibody against toxic tau species induced by injections of tau and Aβ seeds into the mouse brain, two-photon imaging of neuronal and astrocytic activities, and monitoring glutamate release levels. In fact, we aim to construct a comprehensive computational framework, with sufficient complexity, devised based on and validated with experimental data to capture the tauopathy progression, bringing together neuroscientists, biologists, and engineers.