ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-beta1-42.

Published

Journal Article

Amyloid-beta1-42 (Abeta1-42) is crucial to Alzheimer disease (AD) pathogenesis but the conformation of the toxic Abeta species remains uncertain. AD risk is increased by apolipoprotein E4 (apoE4) and decreased by apoE2 compared with the apoE3 isoform, but whether inheritance of apoE4 represents a gain of negative or a loss of protective function is also unresolved. Using hippocampal slices from apoE knockout (apoE-KO) and human apoE2, E3, and E4 targeted replacement (apoE-TR) mice, we found that oligomeric Abeta1-42 inhibited long-term potentiation (LTP) with a hierarchy of susceptibility mirroring clinical AD risk (apoE4-TR > apoE3-TR = apoE-KO > apoE2-TR), and that comparable doses of unaggregated Abeta1-42 did not affect LTP. These data provide a novel link among apoE isoform, Abeta1-42, and a functional cellular model of memory. In this model, apoE4 confers a gain of negative function synergistic with Abeta1-42, apoE2 is protective, and the apoE-Abeta interaction is specific to oligomeric Abeta1-42.

Full Text

Duke Authors

Cited Authors

  • Trommer, BL; Shah, C; Yun, SH; Gamkrelidze, G; Pasternak, ES; Stine, WB; Manelli, A; Sullivan, P; Pasternak, JF; LaDu, MJ

Published Date

  • February 2005

Published In

Volume / Issue

  • 18 / 1

Start / End Page

  • 75 - 82

PubMed ID

  • 15649697

Pubmed Central ID

  • 15649697

International Standard Serial Number (ISSN)

  • 0969-9961

Digital Object Identifier (DOI)

  • 10.1016/j.nbd.2004.08.011

Language

  • eng

Conference Location

  • United States