Multiple publications in recent years have shown that the level of serum cystatin C is a better measure of kidney function than are levels of creatinine. While multiple causes, including inflammation, liver dysfunction, and thyroid dysfunction, affect cystatin C levels, it is currently accepted that elevated cystatin C serum levels mostly reflect a clinical or preclinical state of kidney dysfunction. Several publications, including previous ones by the same authors, have shown that serum cystatin C levels, as an indicator of kidney function, strongly predict risk of disease and mortality in elderly people.
Cystatin C is a cysteine proteinase inhibitor produced by all tissues examined. In the brain it is expressed by astrocytes, microglia, neurons, and the choroids plexus. It is secreted into all mammalian body fluids, and its concentration in the cerebral spinal fluid (CSF) is higher than in the serum, suggesting that CSF cystatin C represents the protein produced in the central nervous system. It is not known whether cystatin C is transported between the brain and the periphery, and whether its concentration in the serum affects its concentration in the central nervous system. Hence, the relationship between the present association of elevated serum cystatin C with unsuccessful aging and prior research on cystatin C brain function remains unclear at present.
The role of cystatin C in the brain is not fully understood, and both protective and toxic effects have been postulated (for review, see Levy, 2006). It has been implicated in the processes of neuronal degeneration and repair of the nervous system. Enhanced cystatin C expression was observed in response to injury, including facial nerve axotomy, perforant path transections, hypophysectomy, transient forebrain ischemia, and induction of epilepsy. In vitro and in vivo data suggest that enhanced cystatin C expression in response to injury protects cells from various types of toxicity.
There are several indications that cystatin C has a role in Alzheimer disease:
1. Genetic data were presented demonstrating linkage of the cystatin C gene (CST3, see AlzGene overview) with an increased risk of developing late-onset Alzheimer disease. The polymorphism in CST3 results in a reduced secretion of cystatin C.
2. Immunohistochemical studies revealed strong dual staining with antibodies to Aβ and to cystatin C in a subpopulation of pyramidal neurons in the prefrontal cortex and hippocampus. Furthermore, colocalization of cystatin C with Aβ was found predominantly in amyloid-laden vascular walls, and in senile plaque cores of amyloid.
3. Cystatin C binds soluble Aβ and inhibits Aβ oligomerization and fibril formation in vitro (Sastre, 2004; Selenica, 2007) and in vivo (Kaeser, 2007; Mi, 2007). We hypothesize that cystatin C is a carrier of soluble Aβ in body fluids such as CSF and blood, as well as in the neuropil. Increased cystatin C concentration, relative to that of Aβ, would serve to prevent Aβ aggregation and fibril formation.
However, cystatin C may induce cerebral hemorrhages. A Leu68Gln variant of cystatin C forms the amyloid deposited in cerebral vascular walls of patients with hereditary cerebral hemorrhage with amyloidosis, Icelandic type. This is an autosomal-dominant form of cerebral amyloid angiopathy (CAA) with recurrent hemorrhagic strokes causing serious brain damage and eventually fatal stroke before the age of 40 (see also ARF related conference story). Cystatin C may also have a role in cerebral hemorrhages involving Aβ CAA. It is still unclear when CAA leads to hemorrhage. Amyloid deposits in the brain vasculature are usually asymptomatic, and only a subpopulation of patients is at high risk of hemorrhage. Thus, CAA appears to be necessary but not sufficient for vessel rupture, with additional factors playing important roles. A role for cystatin C in CAA-related hemorrhage is implicated from immunohistochemical studies that revealed colocalization of cystatin C and Aβ in amyloid-laden vascular walls. Some reports suggested that only patients showing colocalization of cystatin C and Aβ immunoreactivity in their diseased cerebral vessels suffered fatal subcortical hemorrhages. The degree of cerebrovascular amyloid deposition in these patients was also greater than in patients without cerebral hemorrhages.
Cystatin C colocalization with amyloid, other than Aβ, was observed in other disorders, such as hereditary gelsolin amyloidosis (familial amyloidosis, Finnish type) and familial cerebral amyloid angiopathy, British type. Thus, cystatin C may have a role in CAA and hemorrhage in a variety of diseases that involve deposition of heterogeneous types of amyloid proteins (Levy et al., 2006).
In this observational study, Sarnak et al. report that high serum cystatin C levels are associated with unsuccessful aging, measured in part by cognitive dysfunction, in a community-based cohort of adults age 65 and older. These serum levels reflect kidney function. Their role, if any, in the cognitive impairment described in this study population is unclear. Cystatin C has a variety of roles both in the periphery and in the brain. Multiple sets of data suggest that its function—being either protective or toxic—depends on its concentration in specific locations. Therefore, any therapeutic procedure that would use a drug developed to mimic cystatin C protective function, both against Aβ oligomerization and fibril formation and against neurodegeneration, should take into consideration the possible undesirable effect of this protein.
References:
Kaeser SA, Herzig MC, Coomaraswamy J, Kilger E, Selenica ML, Winkler DT, Staufenbiel M, Levy E, Grubb A, Jucker M.
Cystatin C modulates cerebral beta-amyloidosis.
Nat Genet. 2007 Dec;39(12):1437-9.
PubMed.
Levy E, Jaskolski M, Grubb A.
The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models.
Brain Pathol. 2006 Jan;16(1):60-70.
PubMed.
Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky DS, Klein AM, Sommer J, Schmidt SD, Nixon RA, Mathews PM, Levy E.
Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models.
Nat Genet. 2007 Dec;39(12):1440-2.
PubMed.
Sastre M, Calero M, Pawlik M, Mathews PM, Kumar A, Danilov V, Schmidt SD, Nixon RA, Frangione B, Levy E.
Binding of cystatin C to Alzheimer's amyloid beta inhibits in vitro amyloid fibril formation.
Neurobiol Aging. 2004 Sep;25(8):1033-43.
PubMed.
Selenica ML, Wang X, Ostergaard-Pedersen L, Westlind-Danielsson A, Grubb A.
Cystatin C reduces the in vitro formation of soluble Abeta1-42 oligomers and protofibrils.
Scand J Clin Lab Invest. 2007;67(2):179-90.
PubMed.
Comments
Multiple publications in recent years have shown that the level of serum cystatin C is a better measure of kidney function than are levels of creatinine. While multiple causes, including inflammation, liver dysfunction, and thyroid dysfunction, affect cystatin C levels, it is currently accepted that elevated cystatin C serum levels mostly reflect a clinical or preclinical state of kidney dysfunction. Several publications, including previous ones by the same authors, have shown that serum cystatin C levels, as an indicator of kidney function, strongly predict risk of disease and mortality in elderly people.
Cystatin C is a cysteine proteinase inhibitor produced by all tissues examined. In the brain it is expressed by astrocytes, microglia, neurons, and the choroids plexus. It is secreted into all mammalian body fluids, and its concentration in the cerebral spinal fluid (CSF) is higher than in the serum, suggesting that CSF cystatin C represents the protein produced in the central nervous system. It is not known whether cystatin C is transported between the brain and the periphery, and whether its concentration in the serum affects its concentration in the central nervous system. Hence, the relationship between the present association of elevated serum cystatin C with unsuccessful aging and prior research on cystatin C brain function remains unclear at present.
The role of cystatin C in the brain is not fully understood, and both protective and toxic effects have been postulated (for review, see Levy, 2006). It has been implicated in the processes of neuronal degeneration and repair of the nervous system. Enhanced cystatin C expression was observed in response to injury, including facial nerve axotomy, perforant path transections, hypophysectomy, transient forebrain ischemia, and induction of epilepsy. In vitro and in vivo data suggest that enhanced cystatin C expression in response to injury protects cells from various types of toxicity.
There are several indications that cystatin C has a role in Alzheimer disease:
1. Genetic data were presented demonstrating linkage of the cystatin C gene (CST3, see AlzGene overview) with an increased risk of developing late-onset Alzheimer disease. The polymorphism in CST3 results in a reduced secretion of cystatin C.
2. Immunohistochemical studies revealed strong dual staining with antibodies to Aβ and to cystatin C in a subpopulation of pyramidal neurons in the prefrontal cortex and hippocampus. Furthermore, colocalization of cystatin C with Aβ was found predominantly in amyloid-laden vascular walls, and in senile plaque cores of amyloid.
3. Cystatin C binds soluble Aβ and inhibits Aβ oligomerization and fibril formation in vitro (Sastre, 2004; Selenica, 2007) and in vivo (Kaeser, 2007; Mi, 2007). We hypothesize that cystatin C is a carrier of soluble Aβ in body fluids such as CSF and blood, as well as in the neuropil. Increased cystatin C concentration, relative to that of Aβ, would serve to prevent Aβ aggregation and fibril formation.
However, cystatin C may induce cerebral hemorrhages. A Leu68Gln variant of cystatin C forms the amyloid deposited in cerebral vascular walls of patients with hereditary cerebral hemorrhage with amyloidosis, Icelandic type. This is an autosomal-dominant form of cerebral amyloid angiopathy (CAA) with recurrent hemorrhagic strokes causing serious brain damage and eventually fatal stroke before the age of 40 (see also ARF related conference story). Cystatin C may also have a role in cerebral hemorrhages involving Aβ CAA. It is still unclear when CAA leads to hemorrhage. Amyloid deposits in the brain vasculature are usually asymptomatic, and only a subpopulation of patients is at high risk of hemorrhage. Thus, CAA appears to be necessary but not sufficient for vessel rupture, with additional factors playing important roles. A role for cystatin C in CAA-related hemorrhage is implicated from immunohistochemical studies that revealed colocalization of cystatin C and Aβ in amyloid-laden vascular walls. Some reports suggested that only patients showing colocalization of cystatin C and Aβ immunoreactivity in their diseased cerebral vessels suffered fatal subcortical hemorrhages. The degree of cerebrovascular amyloid deposition in these patients was also greater than in patients without cerebral hemorrhages.
Cystatin C colocalization with amyloid, other than Aβ, was observed in other disorders, such as hereditary gelsolin amyloidosis (familial amyloidosis, Finnish type) and familial cerebral amyloid angiopathy, British type. Thus, cystatin C may have a role in CAA and hemorrhage in a variety of diseases that involve deposition of heterogeneous types of amyloid proteins (Levy et al., 2006).
In this observational study, Sarnak et al. report that high serum cystatin C levels are associated with unsuccessful aging, measured in part by cognitive dysfunction, in a community-based cohort of adults age 65 and older. These serum levels reflect kidney function. Their role, if any, in the cognitive impairment described in this study population is unclear. Cystatin C has a variety of roles both in the periphery and in the brain. Multiple sets of data suggest that its function—being either protective or toxic—depends on its concentration in specific locations. Therefore, any therapeutic procedure that would use a drug developed to mimic cystatin C protective function, both against Aβ oligomerization and fibril formation and against neurodegeneration, should take into consideration the possible undesirable effect of this protein.
References:
Kaeser SA, Herzig MC, Coomaraswamy J, Kilger E, Selenica ML, Winkler DT, Staufenbiel M, Levy E, Grubb A, Jucker M. Cystatin C modulates cerebral beta-amyloidosis. Nat Genet. 2007 Dec;39(12):1437-9. PubMed.
Levy E, Jaskolski M, Grubb A. The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models. Brain Pathol. 2006 Jan;16(1):60-70. PubMed.
Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky DS, Klein AM, Sommer J, Schmidt SD, Nixon RA, Mathews PM, Levy E. Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models. Nat Genet. 2007 Dec;39(12):1440-2. PubMed.
Sastre M, Calero M, Pawlik M, Mathews PM, Kumar A, Danilov V, Schmidt SD, Nixon RA, Frangione B, Levy E. Binding of cystatin C to Alzheimer's amyloid beta inhibits in vitro amyloid fibril formation. Neurobiol Aging. 2004 Sep;25(8):1033-43. PubMed.
Selenica ML, Wang X, Ostergaard-Pedersen L, Westlind-Danielsson A, Grubb A. Cystatin C reduces the in vitro formation of soluble Abeta1-42 oligomers and protofibrils. Scand J Clin Lab Invest. 2007;67(2):179-90. PubMed.
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