title: Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity.
abstract: Inheritance of the apolipoprotein (APO) E gene epsilon4 or epsilon2 allele alters the risk of developing Alzheimer disease (AD), while increased alpha-tocopherol (AT) intake appears to lower the risk of AD. As APOE is a major apolipoprotein in the CNS and AT in vivo is transported in lipoproteins, we tested the hypothesis that CNS lipoproteins, as modeled by relevant concentrations of high density lipoprotein (HDL), and AT would interact to suppress neurotoxicity in a cell culture model of amyloid beta (Abeta)- related toxicity. These cells conditionally express C99-derived peptides, proposed to be a key step in AD pathogenesis; this expression is closely associated with subsequent cell death. We found that physiologic concentrations of lipoproteins present in the CNS protected from C99-associated toxicity and provided evidence for two mechanisms of protection. The first was AT-independent, APOE isoform-dependent, and most potent for the APOE2 isoform. The second was a synergistic protection afforded by a combination of APOAI, or less so APOE, and AT. These data provide a novel explanation for the apparent AD-protective effect of inheriting an epsilon2 APOE allele, and suggest that optimizing AT enrichment of CNS lipoproteins or devising APOAI mimetics may augment AT efficacy in treating AD.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98104, USA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000494:pharmacology / Q000502:physiology*; D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000494:pharmacology / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D004357:Drug Synergism; D006801:Humans; D008075:Lipoproteins, HDL / Q000494:pharmacology; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism*; D020033:Protein Isoforms / Q000494:pharmacology / Q000502:physiology; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D016632:Apolipoprotein A-I; D053329:Apolipoprotein E2; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D018696:Neuroprotective Agents; D020033:Protein Isoforms; D024502:alpha-Tocopherol