APP-induced patterned neurodegeneration exacerbated by APOE4 in C. elegans

Abstract

Genetic and epidemiological studies have found that variations in the amyloid precursor protein (APP) and the apoliopoprotein E (APOE) genes represent major modifiers of the progressive neurodegeneration in Alzheimers disease (AD). An extra copy or gain-of-function mutations in APP lower age of AD onset. Compared to the other isoforms (APOE3 and APOE2), the {varepsilon}4 allele of APOE (APOE4) hastens and exacerbates early and late onset forms of AD. Convenient in vivo models to study how APP and APOE4 interact at the cellular and molecular level to influence neurodegeneration are lacking. Here, we show that the nematode C. elegans can model important aspects of AD including age-related, patterned neurodegeneration that is exacerbated by APOE4. Specifically, we found that APOE4, but not APOE3, acts with APP to hasten and expand the pattern of cholinergic neurodegeneration caused by APP. Molecular mechanisms underlying how APP and APOE4 synergize to kill some neurons while leaving others unaffected may be uncovered using this convenient worm model of neurodegeneration.