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Human Molecular Genetics, 2001, Vol. 10, No. 22 2525-2537
© 2001 Oxford University Press

Hyper-expression of human apolipoprotein E4 in astroglia and neurons does not enhance amyloid deposition in transgenic mice

Christian Lesuisse1, Guilian Xu1,4, Jeffery Anderson5, Molly Wong4, Joanna Jankowsky1, Greg Holtz5, Victoria Gonzalez1, Philip C. Y. Wong1, Donald L. Price1,2,3, Fai Tang4, Steve Wagner5 and David R. Borchelt1,2,+

1Department of Pathology, 2Department of Neuroscience and 3Department of Neurology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building—Room 558, Baltimore, MD 21205, USA, 4Department of Physiology, University of Hong Kong, Hong Kong, China and 5Merck Research Laboratories, San Diego, 505 Coast Boulevard South, La Jolla, CA 92037, USA

Recent studies in mice have clearly demonstrated that eliminating Apo E alters the rate, character and distribution of Aß deposits. In the present study, we asked whether elevating the levels of Apo E can, in a dominant fashion, influence amyloid deposition. We expressed human (Hu) Apo E4 via the mouse prion protein promoter, resulting in high expression in both astrocytes and neurons; only astrocytes efficiently secreted Hu Apo E4 (at least 5-fold more than endogenous). Mice hyper-expressing Hu Apo E4 developed normally and lived normal lifespans. The co-expression of Hu Apo E4 with a mutant amyloid precursor protein (APP) (Mo/Hu APPswe) or mutant APP and mutant presenilin (PS1dE9) did not lead to proportional changes in the age of appearance, relative burden, character or distribution of Aß deposits. We suggest that these data are best explained by proposing that the mechanisms by which Apo E influences Aß deposition involves an aspect of its normal function that is not augmented by hyper-expression.

+ To whom correspondence should be addressed. Tel: +1 410 502 5174; Fax: +1 410 955 9777; Email: drbor@jhmi.eduThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First AuthorsPresent address:Steve Wagner, Neurogenetics Inc., San Diego, CA, USA


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