Cystatin C in Alzheimer's disease

Abstract

Changes in expression and secretion levels of cystatin C (CysC) in the brain in various neurological disorders and in animal models of neurodegeneration underscore a role for CysC in these conditions. A polymorphism in the CysC gene (CST3) is linked to increased risk for Alzheimer's disease (AD). AD pathology is characterized by deposition of oligomeric and fibrillar forms of amyloid β (Aβ) in the neuropil and cerebral vessel walls, neurofibrillary tangles composed mainly of hyperphosphorylated tau, and neurodegeneration. The implication of CysC in AD was initially suggested by its co-localization with Aβ in amyloid-laden vascular walls, and in senile plaque cores of amyloid in the brains of patients with AD, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), and cerebral infarction. CysC also co-localizes with Aβ amyloid deposits in the brains of non-demented aged individuals. Multiple lines of research show that CysC plays protective roles in AD. In vitro studies have shown that CysC binds Aβ and inhibits Aβ oligomerization and fibril formation. In vivo results from the brains and plasma of Aβ-depositing transgenic mice confirmed the association of CysC with the soluble, non-pathological form of Aβ and the inhibition of Aβ plaques formation. The association of CysC with Aβ was also found in brain and in cerebrospinal fluid (CSF) from AD patients and non-demented control individuals. Moreover, in vitro results showed that CysC protects neuronal cells from a variety of insults that may cause cell death, including cell death induced by oligomeric and fibrillar Aβ. These data suggest that the reduced levels of CysC manifested in AD contribute to increased neuronal vulnerability and impaired neuronal ability to prevent neurodegeneration. This review elaborates on the neuroprotective roles of CysC in AD and the clinical relevance of this protein as a therapeutic agent.

Role of Cystatin C in Amyloid Precursor Protein-induced Proliferation of Neural Stem/Progenitor Cells

“…It is interesting to note that a polymorphism (G73A) in cystatin C has been linked to AD (43). Furthermore, cystatin C is increased in regions around A␤ deposits in the AD brain (44,45), suggesting that it may play a role in pathogenesis or in response to A␤ pathology. Indeed, two groups, Mi et al (46) and Kaeser et al (47), found that cystatin C may have a protective effect as APP transgenic mice that had higher cystatin C expression were found to have diminished A␤ deposition.…”

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

“…CysC plays a role in different diseases, from cancer to neurodegenerative disorders (66). Mutations of CysC can lead to fatal hereditary cystatin C amyloid angiopathy.…”

“…CysC is thus likely indirectly involved in A␤ regulation. Epidemiologically, a polymor- phism in the CysC gene (CST3) has been linked to enhanced risk for AD (66), and CysC modulates cerebral ␤-amyloidosis in A␤PP transgenic mice (71).…”

Unraveling the genes implicated in Alzheimer's disease

“…In addition, CST3 exerts a protective effect in AD by preventing the formation of toxic forms of Aβ (104). A previous study with transgenic mice demonstrated the association of CST3 with non-toxic forms of Aβ and prevention of Aβ plaque formation (105). In addition, the authors revealed that reduced levels of CST3 may impair the neuronal ability to prevent neurodegeneration in AD (105).…”