THE ASSOCIATION BETWEEN TOXIC AΒ SPECIES AND AXONAL GROWTH AND SPROUTING IN ALZHEIMER'S DISEASE

Studying changes in the brain before amyloid pathology appears and symptom onset occurs could contribute to our understanding of the pathogenesis of Alzheimer’s disease (AD). In our previous studies of the App^NL-F knock-in AD mouse model, we observed changes in neuritogenesis early in the life span of the mouse. Ankyrin-3 (ANK-3), a marker of the axon initial segment is commonly used for studying neuritogenesis. In this study, we aimed to further characterize neuritogenesis in the App^NL-F mouse model and in AD brain by determining a time course of changes in the distribution of ANK-3 in brain tissue and in primary neurons. Moreover, we wanted to investigate the associations between axonal development on localization of the amyloid precursor protein (APP). We used AD brain and brains from embryonic, 6-, 12-, and 25 months old App^NL-F mice for ANK-3 immunolabeling. Additionally, we stained primary hippocampal neurons derived from wild-type and App^NL-F mice for ANK-3 and the C-terminal fragment of APP to assess APP localization in the axon. ANK-3 labeling was increased in the brains of AD patients compared to controls, as well as in 6 months old App^NL-F mice compared to wild-type mice. Our results also indicated differences in levels of ANK-3 and axonal APP in primary hippocampal cultures from App^NL-F compared to wild-type mice. These results suggest that axonal growth and APP localization are influenced by increased Aβ42 levels. We conclude that neuritogenesis is affected in the App^NL-F mouse model and AD, possibly mediated by elevated levels of Aβ42.