Grant: CIHR Fellowship

Dementias, including Alzheimer's disease (AD), are often defined by protein inclusions (proteinopathies), and are increasingly recognized as being mixed pathologies. Approximately 50% of people living with Alzheimer's have additional proteinopathies beyond the classical hallmarks. TDP-43 is a protein that appears prominently in these cases and is a major pathology of frontotemporal dementia, and present in 1/3-1/2 of AD brains. TDP-43, normally in the nucleus, mislocalizes and accumulates in the cytoplasm in disease. Additionally, in AD, TDP-43 pathology is found in brain regions associated with anxiety and memory, and seen in another dementia called limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE). Finally, there is emerging evidence that TDP-43 contributes to psychiatric symptoms like depression and anxiety, and lowers an individual's resilience to dementia. We hypothesize that lived experience stressors compound TDP-43 pathology, impacting neuronal circuits of anxiety and memory, and reducing resilience to stress and proteinopathy. We propose to assess a major stressor in late life, sleep disruption, on proteostasis and TDP-43 pathology, and examine how this can contribute to vulnerability of neurons and brain regions associated with dementia and neuropsychiatric conditions. Using mouse models of Alzheimer's pathology, we have evidence sleep disruption can alter behaviour with unique sex differences. We plan to examine which neuronal types and brain regions have cytoplasmic TDP-43 accumulation, and compare these results to genetic markers of people with AD, with or without TDP-43. This work will greatly improve our understanding of mixed proteinopathies and the dynamics between neuropathology and neuropsychiatric symptoms. With an aging population, it is of the utmost importance to determine how TDP-43 contributes to dementia and depression, and will be a foundation for future diagnostic potential.