Breaking Barriers: A Quantitative Analysis of Axon Initial Segment Damage in Neurodegenerative Diseases

Axon initial segment (AIS) damage has been implicated in several neurodegenerative diseases (NDs). Nevertheless, it is unknown whether systematic damage to the AIS is a unifying feature among Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Parkinson’s disease. In this dissertation, it was hypothesized that 1) AIS structural and functional damage occurs in NDs, 2) extracellular tau oligomers (xcTauO) cause damage to the AIS, and 3) xcTauOs cause AIS protein, tripartite motif-containing protein 46 (TRIM46) and lysosomal-associated membrane protein 1 (LAMP1)+ organelles to co-localize. A systematic literature review, quantitive western blots, and quantitative immunofluorescence were performed. The literature review identified 42 studies that quantified 14 AIS structural and two AIS functional parameters in five NDs. The data chapters found that xcTauOs work through intracellular tau to cause a reduction in AIS immunofluorescent intensity as a semi-quantitative measurement of localized protein abundance and AIS shortening. These same xcTauOs also increase AIS protein, TRIM46, and LAMP1 co-localization. Overall the work presented in this dissertation demonstrates that the AIS can be damaged by xcTauOs in NDs.