Cardona, E. A. | bioRxiv Science

bioRxiv2025

APOE4-induced patterned behavioral decline and neurodegeneration requires endogenous tau in a C. elegans model of Alzheimers disease

Alzheimers disease (AD) causes a characteristic spatiotemporal pattern of neurodegeneration. The factors that account for this pattern of degeneration are unclear. Previously, we generated a model of AD using the nematode Caenorhabditis elegans with the AD risk variant of apolipoprotein E, APOE4. We showed that HSN class neurons degenerate in early adult animals. Here, we perform behavioral analyses to deduce the effect of APOE4 on the function of distinct neuronal circuits. We found evidence that APOE4 induces dysfunction of other neurons; this spatiotemporal pattern roughly correlates with endogenous levels of PTL-1, the C. elegans homolog of human MAPT also known as tau. Moreover, deletion of ptl-1 suppressed defects in multiple behaviors, suggesting broad protective effects across the nervous system including the HSN neurons. Lastly, we show that PTL-1 in the touch receptor neurons, where PTL-1 is most abundant, contributes non-cell autonomously for age-related axon dysmorphia and dysfunction of the HSN neurons. Our results suggest that C. elegans may provide a useful in vivo system to study how endogenous tau acts downstream of APOE4 to cause progressive, patterned neurodegeneration.

neuroscience↗

bioRxiv2024

Non-apoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans

While traditionally studied for their pro-apoptotic functions, recent research suggests BH3-only proteins also have non-apoptotic roles. Here, we find that EGL-1, the BH3-only protein in Caenorhabditis elegans, promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the mechanistic role of BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health. Significance statementBH3-only proteins were known for their function in inducing cell death. Their presence in healthy adult neurons, however, suggests additional roles. Our study focused on the BH3-only protein EGL-1 in the nematode Caenorhabditis elegans, where its apoptotic role was discovered. We reveal a new role in cell-autonomously promoting exopher production - a process where neurons extrude large vesicles containing potentially harmful cell contents. EGL-1 appears to promote this by regulating mitochondrial dynamics. We also report that low levels of EGL-1 benefit neuronal health and function. These findings expand our understanding of BH3-only proteins, mitochondrial dynamics, and exopher production in neurons and provide insights for neurodegenerative diseases.

neuroscience↗