Allele-specific distinctions in the human apolipoprotein E (APOE) locus represent the best-characterized genetic predictor of Alzheimer's disease (AD) risk. Expression of isoform APOEε2 is associated with reduced risk, while APOEε3 is neutral and APOEε4 carriers exhibit increased susceptibility. Using Caenorhabditis elegans, we generated a novel suite of humanized transgenic nematodes to facilitate neuronal modeling of amyloid-beta peptide (Aβ) co-expression in the context of distinct human APOE alleles. We found that co-expression of human APOEε2 with Aβ attenuated Aβ-induced neurodegeneration, whereas expression of the APOEε4 allele had no effect on neurodegeneration, indicating a loss of neuroprotective capacity. Notably, the APOEε3 allele displayed an intermediate phenotype; it was not neuroprotective in young adults but attenuated neurodegeneration in older animals. There was no functional impact from the three APOE isoforms in the absence of Aβ co-expression. Pharmacological treatment that examined neuroprotective effects of APOE alleles on calcium homeostasis showed allele-specific responses to changes in ER-associated calcium dynamics in the Aβ background. Additionally, Aβ suppressed survival, an effect that was rescued by APOEε2 and APOEε3, but not APOEε4. Expression of the APOE alleles in neurons, independent of Aβ, exerted no impact on survival. Taken together, these results illustrate that C. elegans provides a powerful in vivo platform with which to explore how AD-associated neuronal pathways are modulated by distinct APOE gene products in the context of Aβ-associated neurotoxicity. The significance of both ApoE and Aβ to AD highlights the utility of this new pre-clinical model as a means to dissect their functional inter-relationship.This article has an associated First Person interview with the first author of the paper.
Keywords: Alzheimer's disease; ApoE; Aβ; C. elegans; Neurodegeneration.
© 2019. Published by The Company of Biologists Ltd.