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Research and Publications - Department of Biological Sciences

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Browsing Research and Publications - Department of Biological Sciences by Subject "A beta"

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    ApoE-associated modulation of neuroprotection from A beta-mediated neurodegeneration in transgenic Caenorhabditis elegans
    (Company of Biologists, 2019) Griffin, Edward F.; Scopel, Samuel E.; Stephen, Cayman A.; Holzhauer, Adam C.; Vaji, Madeline A.; Tuckey, Ryan A.; Berkowitz, Laura A.; Caldwell, Kim A.; Caldwell, Guy A.; University of Alabama Tuscaloosa; University of Alabama Birmingham
    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 APOE epsilon 2 is associated with reduced risk, while APOE epsilon 3 is neutral and APOE epsilon 4 carriers exhibit increased susceptibility. Using Caenorhabditis elegans, we generated a novel suite of humanized transgenic nematodes to facilitate neuronal modeling of amyloid-beta peptide (A beta) co-expression in the context of distinct human APOE alleles. We found that co-expression of human APOE epsilon 2 with A beta attenuated A beta-induced neurodegeneration, whereas expression of the APOE epsilon 4 allele had no effect on neurodegeneration, indicating a loss of neuroprotective capacity. Notably, the APOE epsilon 3 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 A beta 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 A beta background. Additionally, A beta suppressed survival, an effect that was rescued by APOE epsilon 2 and APOE epsilon 3, but not APOE epsilon 4. Expression of the APOE alleles in neurons, independent of A beta, 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 A beta-associated neurotoxicity. The significance of both ApoE and A beta to AD highlights the utility of this new pre-clinical model as a means to dissect their functional inter-relationship.