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J. Biol. Chem., Vol. 279, Issue 19, 20296-20306, May 7, 2004

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Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid -Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid -Protein Precursor^*

Judianne Davis, Feng Xu, Rashid Deane, Galina Romanov, Mary Lou Previti, Kelly Zeigler, Berislav V. Zlokovic, and William E. Van Nostrand¶

From the Department of Medicine, Health Sciences Center, Stony Brook University, Stony Brook, New York 11794-8153 and the Frank P. Smith Laboratories for Neurosurgery, Department of Neurosurgery and Division of Neurovascular Biology, University of Rochester Medical Center, Rochester, New York 14642

Cerebrovascular deposition of amyloid -protein (A) is a common pathological feature of Alzheimer's disease and related disorders. In particular, the Dutch E22Q and Iowa D23N mutations in A cause familial cerebrovascular amyloidosis with abundant diffuse amyloid plaque deposits. Both of these charge-altering mutations enhance the fibrillogenic and pathogenic properties of A in vitro. Here, we describe the generation of several transgenic mouse lines (Tg-SwDI) expressing human neuronal A precursor protein (APP) harboring the Swedish K670N/M671L and vasculotropic Dutch/Iowa E693Q/D694N mutations under the control of the mouse Thy1.2 promoter. Tg-SwDI mice expressed transgenic human APP only in the brain, but at levels below those of endogenous mouse APP. Despite the paucity of human APP expression, quantitative enzyme-linked immunosorbent assay measurements revealed that Tg-SwDI mice developed early-onset and robust accumulation of A in the brain with high association with isolated cerebral microvessels. Tg-SwDI mice exhibited striking perivascular/vascular A deposits that markedly increased with age. The vascular A accumulations were fibrillar, exhibiting strong thioflavin S staining, and occasionally presented signs of microhemorrhage. In addition, numerous largely diffuse, plaque-like structures were observed starting at 3 months of age. In vivo transport studies demonstrated that Dutch/Iowa mutant A was more readily retained in the brain compared with wild-type A. These results with Tg-SwDI mice demonstrate that overexpression of human APP is not required for early-onset and robust accumulation of both vascular and parenchymal A in mouse brain.

Received for publication, November 26, 2003 , and in revised form, February 19, 2004.

^* This work was supported by National Institutes of Health Grants NS36645 (to W. E. V. N.), NS34467 (to B. V. Z.), and AG16233 (to B. V. Z. and W. E. V. N.) and by Alzheimer's Association Grant IIRG-02-3995 (to W. E. V. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Medicine, Health Sciences Center, T-15/081, Stony Brook University, Stony Brook, NY 11794-8153. Tel.: 631-444-1661; Fax: 631-444-7518; E-mail: William.VanNostrand{at}stonybrook.edu.

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