Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor*
- Judianne Davis‡,
- Feng Xu‡,
- Rashid Deane§,
- Galina Romanov‡,
- Mary Lou Previti‡,
- Kelly Zeigler‡,
- Berislav V. Zlokovic§ and
- William E. Van Nostrand‡¶
- ‡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
- ¶ 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.
Abstract
Cerebrovascular deposition of amyloid β-protein (Aβ) is a common pathological feature of Alzheimer's disease and related disorders. In particular, the Dutch E22Q and Iowa D23N mutations in Aβ cause familial cerebrovascular amyloidosis with abundant diffuse amyloid plaque deposits. Both of these charge-altering mutations enhance the fibrillogenic and pathogenic properties of Aβ in vitro. Here, we describe the generation of several transgenic mouse lines (Tg-SwDI) expressing human neuronal Aβ precursor protein (AβPP) 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 AβPP only in the brain, but at levels below those of endogenous mouse AβPP. Despite the paucity of human AβPP expression, quantitative enzyme-linked immunosorbent assay measurements revealed that Tg-SwDI mice developed early-onset and robust accumulation of Aβ in the brain with high association with isolated cerebral microvessels. Tg-SwDI mice exhibited striking perivascular/vascular Aβ deposits that markedly increased with age. The vascular Aβ 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 Aβ was more readily retained in the brain compared with wild-type Aβ. These results with Tg-SwDI mice demonstrate that overexpression of human AβPP is not required for early-onset and robust accumulation of both vascular and parenchymal Aβ in mouse brain.
Footnotes
-
↵1 The abbreviations used are: Aβ, amyloid β-protein; AβPP, amyloid β-protein precursor; CAA, cerebral amyloid angiopathy; Tg-SwDI, transgenic mouse expressing human Swedish, Dutch, and Iowa triple mutant AβPP; ELISA, enzyme-linked immunosorbent assay; HPLC, high pressure liquid chromatography; Tricine, N-[2-hydroxy-1, 1-bis(hydroxymethyl)ethyl]glycine.
-
↵* 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.
-
- Received November 26, 2003.
- Revision received February 19, 2004.
- The American Society for Biochemistry and Molecular Biology, Inc.
