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(Stroke. 2000;31:534.)
© 2000 American Heart Association, Inc.

Original Contributions

Toxicity of Dutch (E22Q) and Flemish (A21G) Mutant Amyloid ß Proteins to Human Cerebral Microvessel and Aortic Smooth Muscle Cells

Zhenzhen Wang, MD, PhD; Remco Natté, MD; Judith A. Berliner, PhD; Sjoerd G. van Duinen, MD, PhD Harry V. Vinters, MD

From the Department of Pathology and Laboratory Medicine (Neuropathology) (Z.W., H.V.V.), Department of Pathology and Laboratory Medicine (J.A.B.), and Brain Research Institute, Mental Retardation Research Center and Neuropsychiatric Institute (H.V.V.), University of California at Los Angeles School of Medicine; and Departments of Neurology and Pathology, Leiden University Medical Center (Netherlands) (R.N., S.G. van D.).

Background and Purpose—Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid ß protein (Aß) in cortical and leptomeningeal vessels of patients with Alzheimer’s disease and hereditary cerebral hemorrhage with amyloidosis, Dutch type. Smooth muscle cells (SMC) from cerebral microvessels (MV) are of particular interest as a site of Aß-related injury because CAA is much more pronounced in the tunica media of cortical arterioles than meningeal arteries. Patients carrying point mutations at residues 22 (E22Q) and 21 (A21G) of Aß show severe CAA with various degrees of brain parenchymal Aß deposition. The purpose of this study was to investigate the effects of 2 mutant E22Q- and A21G-Aß peptides on MV and aortic SMC.

Methods—SMC were isolated from human cerebral MV and aorta. Cell morphology, viability, and proliferation as parameters of Aß toxicity were investigated after 3 days of peptide treatment by trypan blue exclusion and [³H]thymidine incorporation.

Results—E22Q-Aß induced significant decreased cellular proliferation and viability, as well as obvious degeneration of both MV and aortic SMC. A21G-Aß and wild-type Aß did not cause significant toxicity, as judged by cell morphology, viability, or cell proliferation, on either type of SMC.

Conclusions—E22Q-Aß induced greater toxicity in all parameters than A21G-Aß and wild-type Aß with respect to both MV and aortic SMC. A21G-Aß did not show a significant toxic effect on MV and aortic SMC. This differential effect may be linked to cell type–specific processing and metabolism of mutant forms of Aß. Mutations in amyloid precursor protein may lead to CAA by different pathogenetic mechanisms or share an unknown property that distinguishes them from wild-type Aß.

Editorial Comment

William I. Rosenblum, MD, Guest Editor

Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia

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