Advanced glycation endproduct precursor alters intracellular amyloid- β/AβPP carboxy-terminal fragment aggregation and cytotoxicity

Randall L. Woltjer, Izumi Maezawa, Joyce J. Ou, Kathleen S. Montine, Thomas J. Montine

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Carbonyl stress from products of lipid peroxidation, such as 4-hydroxynonenal (HNE), and products of sugars in diabetes mellitus, such as methylglyoxal (MG) and glyoxal (G), may contribute to neurodegeneration in Alzheimer's disease (AD). We tested the hypothesis that these carbonyls alter the proposed central pathogenic mechanism of AD, intracellular amyloid-β (Aβ)-mediated cytotoxicity, using a human neuroblastoma cell line that conditionally expresses carboxy-terminal fragments (CTFs) of the amyloid precursor protein. HNE was a potent cytotoxin, whereas G was mildly cytotoxic; cytotoxicity from each was independent of Aβ/CTF expression and not altered by α-tocopherol. In contrast, MG cytotoxicity was enhanced by the induced expression of Aβ/CTFs and suppressed by α-tocopherol, α-tocopherol cytoprotection was accompanied by decreased Aβ/CTF aggregation. G also promoted Aβ/CTF aggregation but by mechanisms unaffected by α-tocopherol treatment. Our findings showed that Aβ/ CTF aggregation and cytotoxicity may be profoundly altered by aldehydes associated with diabetes and that in the case of MG, this process is suppressed by α-tocopherol. Moreover, our results suggest that while intracellular aggregation of Aβ/CTFs may be necessary for the development of toxicity attributable to their expression in this model, the presence of high-molecular weight aggregated Aβ/CTFs does not invariably lead to cytotoxicity.

Original languageEnglish (US)
Pages (from-to)467-476
Number of pages10
JournalJournal of Alzheimer's Disease
Volume5
Issue number6
StatePublished - Dec 2003
Externally publishedYes

Keywords

  • Aggregation
  • Alzheimer's
  • Amyloid
  • Diabetes
  • Glyoxal
  • HNE
  • Methylglyoxal
  • Tocopherol

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology

Fingerprint Dive into the research topics of 'Advanced glycation endproduct precursor alters intracellular amyloid- β/AβPP carboxy-terminal fragment aggregation and cytotoxicity'. Together they form a unique fingerprint.

  • Cite this