Cystatin C. Icelandic-like mutation in an animal model of cerebrovascular beta-amyloidosis.
OBJECTIVE
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-beta 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-beta anti-bodies, 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.
Department of Pharmacology, New York University Medical Center, NY, USA.
L H
LH
Wei
L C
LC
Walker
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Levy
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics*; D002556:Cerebrospinal Fluid Proteins / Q000235:genetics; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics*; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics*; D018076:DNA, Complementary / Q000737:chemistry*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009154:Mutation; D012589:Sciuridae; D013045:Species Specificity
C525030:CST3 protein, human; D002556:Cerebrospinal Fluid Proteins; D055316:Cystatin C; D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D018076:DNA, Complementary