Thesis Format

Monograph

Investigating Cognitive Impairment in TDP-43 Mouse Models of FTD-ALS Using Automated Touchscreens

Keon Coleman, The University of Western OntarioFollow

Degree

Master of Science

Program

Neuroscience

Supervisor

Bussey, Timothy J.

Abstract

TAR-DNA-binding protein 43 (TDP-43) misfolding and aggregation is a major pathological hallmark of frontotemporal dementia-amyotrophic lateral sclerosis (FTD/ALS). FTD/ALS is characterized by motor and cognitive impairment, with cognitive impairment frequently reported before the onset of classical motor symptoms. Yet, treatment for cognitive decline in FTD/ALS is lacking, and robust cognitive phenotypes related to TDP-43 proteinopathy have not been established for most mouse models of FTD/ALS. Herein, we used automated touchscreen technology to assess executive function (affected in FTD/ALS) in male TDP-43^Q331Klow and ^-G348C FTD/ALS transgenic mice. The touchscreen pairwise visual discrimination task revealed impairments in 4-5-month-old TDP-43^Q331Klow and ^-G348C mutants during acquisition and reversal phases. These cognitive impairments manifested prior to motor symptoms. This pattern of results is highly similar to observations in human FTD/ALS. Together, these findings identify the combination of TDP-43 mouse models and touchscreen tests as potentially useful tools for understanding and developing cognitive therapies in FTD/ALS.

Summary for Lay Audience

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are interconnected and incurable progressive neurodegenerative diseases. ALS is characterized by brain and spinal cord neuronal death leading to loss of control over voluntary movement, consistently resulting in paralysis. Eventually, respiratory failure ensues from involuntary muscles becoming affected (e.g., diaphragm), with patients succumbing to the disease within 3-5 years. Those afflicted by FTD experience cognitive dysfunction (e.g., attention and memory), which negatively impacts their personality and social and professional behaviours. The cause of FTD is unknown; however, in 45% of cases functional alterations of a protein called TDP-43 is detected during autopsies. Intriguingly, aggregated TDP-43 is detected in 95% of ALS cases, irrespective of mutations related to ALS. Furthermore, ALS symptoms (e.g., motor impairments) are detected in FTD (~15%), and FTD symptoms (e.g., cognitive impairments), are frequently detected in ALS (~60-70%). Moreover, cognitive impairment is often reported before detection of motor dysfunction symptoms in ALS. Replicating key human FTD/ALS features in TDP-43 mouse models is essential for understanding and developing treatments for FTD/ALS. We explored whether we could detect cognitive alterations and/or motor impairments caused by the insertion of human TDP-43 protein into mice. We utilized a touchscreen system adapted for mice, which allows us to assess cognition in mice in the same way as in humans, facilitating cross-species comparisons. During testing we observed FTD/ALS-like cognitive deficits in TDP-43 mutant mice, consistent with cognitive deficits prominent in human FTD/ALS. Furthermore, the cognitive deficits observed in TDP-43 mutant mice manifested before the onset of any motor impairments related to FTD/ALS. Together these findings suggest that the TDP-43 mutant mice are able to recapitulate some key features of human FTD/ALS, showing that such models may be very useful for the development of cognitive therapies and drug treatments for human FTD/ALS.

Recommended Citation

Coleman, Keon, "Investigating Cognitive Impairment in TDP-43 Mouse Models of FTD-ALS Using Automated Touchscreens" (2020). Electronic Thesis and Dissertation Repository. 7430.
https://ir.lib.uwo.ca/etd/7430