Abstract
Immunohistochemical studies have revealed that cystatin C (CysC) co-localizes with amyloid-β (Αβ) in amyloid-laden vascular walls and in the senile plaque cores of amyloid. In vitro and in vivo animal studies suggest that CysC protects against neurodegeneration by inhibition of cysteine proteases, inhibition of Αβ aggregation, induction of autophagy and induction of cell division. CysC levels may be altered and may have a potential link with cerebrospinal fluid (CSF) Aβ levels in various types of dementia with characteristic amyloid deposits, such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and the atrophic form of general paresis (AF-GP). We assessed the serum and CSF levels of CysC and the CSF levels of Aβ40 and Aβ42 in patients with AD (n = 51), DLB (n = 26) and AF-GP (n = 43) and normal controls (n = 30). Using these samples, we explored the correlation between CSF CysC and CSF Aβ levels. We found that in comparison to the normal control group, both CSF CysC and CSF Aβ42 levels were significantly lower in all three dementia groups (all p<0.001); serum CysC levels were the same in the AD and DLB groups, and were lower in the AF-GP group (p = 0.008). The CSF CysC levels were positively correlated with both the CSF Aβ40 and Aβ42 levels in the AD, AF-GP and normal control groups (r = 0.306∼0.657, all p<0.05). Lower CSF CysC levels might be a common feature in dementia with characteristic amyloid deposits. Our results provide evidence for the potential role of CysC involvement in Aβ metabolism and suggest that modulation of the CysC level in the brain might produce a disease-modifying effect in dementia with characteristic amyloid deposits.
Highlights
Cystatin C (CysC) is secreted by all human cells and found in all mammalian body fluids and tissues
We found a lower percentage of female patients (p,0.001) and younger ages (p,0.001) in the atrophic form of general paresis (AF-general paresis (GP)) group compared to the normal control group (Table 1)
The Geriatric Depression Scale (GDS) scores were significantly higher in the dementia with Lewy bodies (DLB) (p,0.001) and AF-GP (p,0.001) groups compared with the normal control group (Table 2)
Summary
Cystatin C (CysC) is secreted by all human cells and found in all mammalian body fluids and tissues. It is almost completely cleared from the circulation by glomerular ultrafiltration [1]. CysC is involved in many pathological processes, including oxidative stress, neurodegeneration and inflammation [1,2]. A growing number of studies have demonstrated that CysC plays important protective roles in neurodegenerative diseases via various mechanisms [3,4]. In vitro and in vivo animal studies show that CysC plays an ongoing role in the inhibition of amyloid-b (Ab) oligomerization and fibril formation by binding both Ab40 and Ab42 in a specific, saturable and high-affinity manner [5,6]. CysC induces a fully functional autophagy via the mTOR pathway in cells under basal conditions, and enhances the autophagic activation in cells exposed to nutritional deprivation and oxidative stress [9]
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