Reduction of Abeta accumulation in the Tg2576 animal model of Alzheimer's disease after oral administration of the phosphatidyl-inositol kinase inhibitor wortmannin.

S. J. Haugabook, T. Le, D. Yager, B. Zenk, B. M. Healy, E. A. Eckman, C. Prada, L. Younkin, P. Murphy, I. Pinnix, L. Onstead, K. Sambamurti, T. E. Golde, D. Dickson, S. G. Younkin, C. B. Eckman

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

The abnormal accumulation of the amyloid beta protein (Abeta) has been implicated as an early and critical event in the etiology and pathogenesis of Alzheimer's disease (AD). Compounds that reduce Abeta accumulation may therefore be useful therapeutically. In cell-based screens we detected a significant reduction in Abeta concentration after treatment with the phosphatidylinositol kinase inhibitors wortmannin and LY294002. To determine the effect of this class of compounds on in vivo Abeta accumulation, we administered wortmannin to the Tg2576 mouse model of AD. Oral administration of wortmannin over four months resulted in a significant, non-overlapping 40%-50% reduction in the number of senile plaques, one of the pathological hallmarks of AD. Sandwich ELISA analysis of formic acid extractable Abeta in the brain of treated animals indicates that both Abeta40 and the longer, more amyloidogenic form of the peptide, Abeta42, were significantly reduced. These data provide the first direct evidence that compounds identified by their ability to reduce Abeta concentration in vitro can reduce Abeta accumulation and deposition in the brain, thus establishing a basic paradigm for the identification and evaluation of additional compounds that lower Abeta accumulation.

Original languageEnglish (US)
Pages (from-to)16-18
Number of pages3
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume15
Issue number1
DOIs
StatePublished - Jan 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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