Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity

Izumi Maezawa, Lee Way Jin, Randall (Randy) Woltjer, Nobuyo Maeda, George M. Martin, Thomas J. Montine, Kathleen S. Montine

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Inheritance of the apolipoprotein (APO) E gene ε4 or ε2 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 (Aβ)- 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 ε2 APOE allele, and suggest that optimizing AT enrichment of CNS lipoproteins or devising APOAI mimetics may augment AT efficacy in treating AD.

Original languageEnglish (US)
Pages (from-to)1312-1321
Number of pages10
JournalJournal of Neurochemistry
Volume91
Issue number6
DOIs
StatePublished - Dec 2004
Externally publishedYes

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Amyloid beta-Protein Precursor
Apolipoprotein A-I
alpha-Tocopherol
Apolipoproteins E
Cytotoxicity
Protein Isoforms
Alzheimer Disease
Lipoproteins
Toxicity
Alleles
Apolipoprotein E2
Apolipoprotein E4
Apolipoproteins
Cell death
HDL Lipoproteins
Cell culture
Amyloid
Cell Death
Cell Culture Techniques
Genes

Keywords

  • Alpha-tocopherol
  • APO
  • Apolipoproteins
  • C99
  • HDL

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity. / Maezawa, Izumi; Jin, Lee Way; Woltjer, Randall (Randy); Maeda, Nobuyo; Martin, George M.; Montine, Thomas J.; Montine, Kathleen S.

In: Journal of Neurochemistry, Vol. 91, No. 6, 12.2004, p. 1312-1321.

Research output: Contribution to journalArticle

Maezawa, Izumi ; Jin, Lee Way ; Woltjer, Randall (Randy) ; Maeda, Nobuyo ; Martin, George M. ; Montine, Thomas J. ; Montine, Kathleen S. / Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity. In: Journal of Neurochemistry. 2004 ; Vol. 91, No. 6. pp. 1312-1321.
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