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(Stroke. 1996;27:2080-2085.)
© 1996 American Heart Association, Inc.

Articles

Cystatin C

Icelandic-Like Mutation in an Animal Model of Cerebrovascular ß-Amyloidosis

LiHong Wei, MD; Lary C. Walker, PhD Efrat Levy, PhD

the Departments of Pharmacology (E.L., L.W.) and Pathology (E.L.), New York University Medical Center, New York, NY; and the Department of Neuroscience Pharmacology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert, Ann Arbor, Mich (L.C.W.).

Correspondence to Efrat Levy, PhD, New York University Medical Center, 550 First Ave, MSB249, New York, NY. E-mail levye01@mcrcr.med.nyu.edu.

Background and Purpose Cerebral amyloid angiopathy (CAA) occurs as a sporadic disorder in aged humans, as a frequent component of Alzheimer's disease, or in hereditary cerebral hemorrhage with amyloidosis (HCHWA). The primary histological locus of cerebral amyloid deposition varies in aged humans and in different species of nonhuman primates. In aged rhesus monkeys, amyloid deposition occurs most frequently in senile plaques, whereas in aged squirrel monkeys CAA is more common. We hypothesized that the preponderance of CAA in squirrel monkeys is related to a species-specific amino acid change in cystatin C, a cysteine protease inhibitor, similar to the Leu68Gln substitution found in the amyloid protein of Icelandic patients with HCHWA-I, also termed hereditary cystatin C amyloid angiopathy.

Methods We performed immunohistochemical analyses of brain sections of aged squirrel and rhesus monkeys with anti–amyloid-ß and anti–cystatin C antibodies and sequenced the cystatin C cDNA of these monkeys.

Results Cerebral amyloid in aged squirrel and rhesus monkeys, previously shown to be immunoreactive with anti–amyloid-ß antibodies, reacts also with antibodies to cystatin C. While the predicted amino acid sequence in rhesus monkeys differs from the human sequence by four residues, that of the squirrel monkeys has seven additional amino acid substitutions, one of which is Leu68Met.

Conclusions The presence of a mutation in squirrel monkeys similar to the one found in HCHWA-I suggests that alterations in cystatin C may influence the likelihood that amyloid will be deposited in the walls of cerebral blood vessels. These observations support the utilization of the monkeys as models to study CAA.

Editorial Comment

Icelandic-Like Mutation in an Animal Model of Cerebrovascular ß-Amyloidosis

William I. Rosenblum, MD, Guest Editor

Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Va

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