Aβ40 inhibits amyloid deposition in vivo

Jungsu Kim, Luisa Onstead, Suzanne Randle, Robert Price, Lisa Smithson, Craig Zwizinski, Dennis W. Dickson, Todd Golde, Eileen McGowan

Research output: Contribution to journalArticle

253 Scopus citations

Abstract

Numerous studies have established a pivotal role for Aβ42 in Alzheimer's disease (AD) pathogenesis. In contrast, although Aβ40 is the predominant form of amyloid β(Aβ) produced and accumulates to a variable degree in the human AD brain, its role in AD pathogenesis has not been established. It has generally been assumed that an increase in Aβ40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-Aβ40 mice that selectively express high levels of Aβ40 with both Tg2576 (APPswe, K670N+M671L) mice and BRI-Aβ42A mice expressing Aβ42 selectively and analyzed parenchymal and cerebrovascular Aβ deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of Aβ40 decreased Aβ deposition by 60-90%. These results demonstrate that Aβ42 and Aβ40 have opposing effects on amyloid deposition: Aβ42 promotes amyloid deposition but Aβ40 inhibits it. In addition, increasing Aβ40 levels protected BRI-Aβ40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of Aβ40 with respect to amyloid deposition suggest that strategies that preferentially target Aβ40 may actually worsen the disease course and that selective increases in Aβ40 levels may actually reduce the risk for development of AD.

Original languageEnglish (US)
Pages (from-to)627-633
Number of pages7
JournalJournal of Neuroscience
Volume27
Issue number3
DOIs
StatePublished - Jan 17 2007

Keywords

  • Aggregation
  • Alzheimer's disease
  • Amyloid β
  • Cerebral amyloid angiopathy
  • Premature death
  • Transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Kim, J., Onstead, L., Randle, S., Price, R., Smithson, L., Zwizinski, C., Dickson, D. W., Golde, T., & McGowan, E. (2007). Aβ40 inhibits amyloid deposition in vivo. Journal of Neuroscience, 27(3), 627-633. https://doi.org/10.1523/JNEUROSCI.4849-06.2007