ApoE-associated modulation of neuroprotection from A beta-mediated neurodegeneration in transgenic Caenorhabditis elegans

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dc.contributor.authorGriffin, Edward F.
dc.contributor.authorScopel, Samuel E.
dc.contributor.authorStephen, Cayman A.
dc.contributor.authorHolzhauer, Adam C.
dc.contributor.authorVaji, Madeline A.
dc.contributor.authorTuckey, Ryan A.
dc.contributor.authorBerkowitz, Laura A.
dc.contributor.authorCaldwell, Kim A.
dc.contributor.authorCaldwell, Guy A.
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.contributor.otherUniversity of Alabama Birmingham
dc.date.accessioned2023-09-29T12:44:54Z
dc.date.available2023-09-29T12:44:54Z
dc.date.issued2019
dc.description.abstractAllele-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.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationGriffin, E. F., Scopel, S. E., Stephen, C. A., Holzhauer, A. C., Vaji, M. A., Tuckey, R. A., Berkowitz, L. A., Caldwell, K. A., & Caldwell, G. A. (2019). ApoE-associated modulation of neuroprotection from Aβ-mediated neurodegeneration in transgenic Caenorhabditis elegans. Disease Models & Mechanisms. https://doi.org/10.1242/dmm.037218
dc.identifier.doi10.1242/dmm.037218
dc.identifier.orcidhttps://orcid.org/0000-0002-8283-9090
dc.identifier.orcidhttps://orcid.org/0000-0003-1580-6122
dc.identifier.orcidhttps://orcid.org/0000-0003-2096-7924
dc.identifier.urihttps://ir.ua.edu/handle/123456789/12346
dc.languageEnglish
dc.language.isoen_US
dc.publisherCompany of Biologists
dc.subjectApoE
dc.subjectA beta
dc.subjectNeurodegeneration
dc.subjectAlzheimer's disease
dc.subjectC. elegans
dc.subjectAPOLIPOPROTEIN-E
dc.subjectALZHEIMERS-DISEASE
dc.subjectAMYLOID PEPTIDE
dc.subjectALPHA-SYNUCLEIN
dc.subjectC-ELEGANS
dc.subjectLIFE-SPAN
dc.subjectDOPAMINERGIC NEURODEGENERATION
dc.subjectENDOCYTIC TRAFFICKING
dc.subjectBEHAVIORAL DEFICITS
dc.subjectINDUCED AUTOPHAGY
dc.subjectCell Biology
dc.subjectPathology
dc.titleApoE-associated modulation of neuroprotection from A beta-mediated neurodegeneration in transgenic Caenorhabditis elegansen_US
dc.typeArticle
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