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

Alzheimer's disease (AD) causes a characteristic spatiotemporal pattern of neurodegeneration, resulting in the loss of associated faculties such as cognition. The factors which account for this pattern of degeneration are unclear, as AD risk genes are numerous and often broadly expressed. Previously, we generated a model of AD using the nematode Caenorhabditis elegans in which the AD risk variant of apolipoprotein E, APOE4, is pan-neuronally expressed. We showed that HSN class motor neurons degenerate in early adult. Here, we expand on our past work by performing 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 of degeneration 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, is required cell nonautonomously for degeneration 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.