Overexpression of human cystatin C in transgenic mice does not affect levels of endogenous brain amyloid Beta Peptide.
Cystatin C, an inhibitor of cysteine proteases, colocalizes with amyloid beta (Abeta) in parenchymal and vascular amyloid deposits in brains of Alzheimer's disease (AD) patients, suggesting that cystatin C has a role in AD. Cystatin C also colocalizes with beta amyloid precursor protein (betaAPP) in transfected cultured cells. In vitro analysis of the association between the two proteins revealed that binding of cystatin C to full-length betaAPP does not affect the level of Abeta secretion. Here we studied the effect of in vivo overexpression of cystatin C on the levels of endogenous brain Abeta. We have generated lines of transgenic mice expressing either wild-type human cystatin C or the Leu68Gln variant that forms amyloid deposits in the cerebral vessels of Icelandic patients with hereditary cerebral hemorrhage, under control sequences of the human cystatin C gene. Western blot analysis of brain homogenates was used to select lines of mice expressing various levels of the transgene. Analysis of Abeta40 and Abeta42 concentrations in the brain showed no difference between transgenic mice and their nontransgenic littermates. Thus, in vivo overexpression of human cystatin C does not affect Abeta levels in mice that do not deposit Abeta.
Pawlik
Monika
M
Department of Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
Sastre
Magdalena
M
Calero
Miguel
M
Mathews
Paul M
PM
Schmidt
Stephen D
SD
Nixon
Ralph A
RA
Levy
Efrat
E
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C525030:CST3 protein, human; C525031:Cst3 protein, mouse; D055316:Cystatin C; D015891:Cystatins; D003546:Cysteine Endopeptidases