Geneva Proteomics Centre: Research activities
Our goal is to develop, improve and automate protein identification and characterization methodologies using 2-DE, mass spectrometry and bioinformatics and to further apply them in the identification of specific disease associated markers and new therapeutic targets.
The Alzheimer's project
Alzheimer Disease (AD) is an increasingly prevalent form of neurodegeneration that accounts for approximately 50-60% of the overall cases of dementia among people over 65 years of age. Currently a diagnosis of AD requires a careful medical history and physical examination; a detailed neurological and psychiatric examination. However, a definitive diagnosis of AD can only be achieved by post-mortem examination of the brain. Therefore, there is a need for a simple, objective biochemical test which can detect AD at an early stage and which can distinguish AD from other dementia-causing illnesses. In our attempt to find new biochemical markers of AD, we have found a protein differentially expressed in the CSF of AD patients compared to other dementia causing illnesses. This protein is the human cystatin C previously called b trace or post- b globulin. Initially described in 1961 in cerebrospinal fluid, cystatin C is a small cystein proteinase inhibitor present in all human body fluids at physiologically relevant concentrations. The physiological role of cystatin C is likely to regulate extracellular cysteine protease activity, which result from microbial invasion or release of lysosomal proteinases from dying or diseased cells. Cystatin C colocalizes with b-amyloid (A b) within the arteriolar walls in AD brains and cerebral amyloid angiopathy [Levy E 2001]. There are two common haplotypes of the CST3 gene coding for cystatin C (A and B) that differ from each other at three sites: two single base pair changes in the promoter region and one in the signal peptide domain that causes an amino acid substitution (alanine to threonine). Recently, case control studies found associations of CST3 with increase risk of late onset AD [Crawford FC 2000, Finckh U 2000, Beyer K 2001]. Finally, The L68Q mutation of cystatin C causes hereditary cerebral hemorrhage with amyloidosis-Icelandic type (HCHWA-I) [Levy E, 1998], in which accumulation of cystatin C in blood vessel walls leads to progressive loss of smooth muscle cells, microvascular degeneration and cerebral hemorrhage [Wang ZZ 1997]. In the present study, we have studied the different isoforms of human cystatin C present in the CSF. Our results show that an evidence for an association of the N-terminal truncated cystatin C with dementia could be used in order to distinguish AD from other dementia illnesses.
Last modified 18/Sep/2002 by CHH
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