Grant: Master's Award: Canada Graduate Scholarships

Glutamate clearance is vital for maintaining healthy brain function, as excessive glutamate receptor activation at synapses can have neurotoxic effects, contributing to a range of brain diseases, with Alzheimer disease (AD) being the most prominent. This overstimulation is associated with synapse loss, a key correlate of cognitive decline in AD. The primary mechanism for glutamate clearance at the synapse is through excitatory amino acid transporters, with GLT-1 being the most abundant. Most GLT-1 is localized on astrocytes, which are glial cells adjacent to the synapse. Previous studies have also suggested that up-regulation of GLT-1 can reduce amyloid-beta plaque levels, one of the hallmark pathological features of AD. Thus, up-regulating GLT-1 on astrocytes could potentially mitigate or delay the development of the AD-like phenotype in an AD mouse model. For this study, I am injecting 4-month-old Alzheimer's disease mouse models and wild type mice with an adeno-associated virus (AAV) that includes GLT-1. Injecting at 4- months allows for the over-expression of GLT-1 to start at the early stages of progression of the disease. At 12-13 months of age, the mice will be put through experiments. This is an age where synapse loss as well as the two pathological hallmarks of AD would be apparent. It is expected that our selective GLT-1 over-expression would produce benefits for these symptoms. Considering postmortem human studies of AD have shown a reduction in GLT-1, especially in astrocytes, there is potential for eventual human translation to AD patients.