Sun B, Zhou Y, Halabisky B, Lo I, Cho SH, Mueller-Steiner S, Devidze N, Wang X, Grubb A, Gan L. Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron. 2008 Oct 23;60(2):247-57. PubMed.
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Cystatin C has numerous and diverse roles via mechanisms that are either dependent or independent of cathepsin inhibition. In vitro experiments have indicated that it can inhibit the cysteine proteases cathepsins B, H, L, and S. Cystatin C is expressed by all tissues studied and secreted into all body fluids. Because it is present in high concentration in the CNS, it has been suggested that it has an important role as a cysteine protease inhibitor. However, mechanisms that are independent of cathepsin inhibition such as neuroproliferation were previously demonstrated. Furthermore, we have demonstrated that cystatin C binds to amyloid-β and inhibits amyloid-β fibril formation and oligomerization. This was shown in vitro and in mouse models overexpressing human cystatin C. Cystatin C overexpression in these mice does not affect cathepsin B expression and activity. Moreover, the polymorphism in the cystatin C gene that was liked to increased risk of late-onset Alzheimer disease involves a moderate reduction in cystatin C secretion. Alternatively, the complete absence of cystatin C in knockout mice results in increased activity of cathepsin B and enables the identification of the possible role of this enzyme in amyloid-β degradation. The significance of such a role for cathepsin B in the human brain, where high levels of cystatin C are present, remains to be demonstrated.
View all comments by Efrat LevyHertie Institute for Clinical Brain Research, University of Tübingen, and DZNE Tübingen
It seems that there are two mechanisms by which CysC may regulate cerebral β-amyloidosis. One of them we and Efrat Levy’s group described previously in Nature Genetics (Mi et al., 2007; Kaeser et al., 2007), where CysC interacts directly with Aβ fibril formation and deposition. The other is described in the present study, where cystatin C regulates the proteolysis of Aβ via CatB.
The CST3 25Thr allele has been associated with an increased risk of AD. Mechanistically, it was suggested that the 25Thr variant disturbs intracellular cystatin C processing, resulting in impaired CysC secretion and reduced levels of extracellular cystatin C. This is consistent with the lower levels of CysC observed in the plasma of 25Thr allele carriers. These observations are rather in line with the findings in Nature Genetics and are somewhat in contrast with those of Li Gan et al., since the authors do not provide data showing that such an intracellular elevation of CysC would increase Aβ levels. In fact, one would have to challenge whether this retained cystatin C would still be functional in inhibiting proteases like CatB, because the overall processing seems to be impaired. However, this does not mean the findings of Li Gan are not relevant; it just may suggest that one mechanism dominates over the other in AD brains.
Nevertheless, there are some intriguing questions to solve before the above conclusion can be drawn. First, we have, together with Paul Mathews and Anders Grubb, looked at endogenous mouse Aβ levels in CysC-/- mice and did not find any change in the level of mouse Aβ compared to wild-type CysC+/+ mice. Thus, after the work of Gan et al., one would have to conclude that the CatB effect is specific to human Aβ, which is very interesting but also unexpected. Hence, it would be nice to see what happens if mouse CysC is overexpressed. Second, we reported in our Nature Genetics work, in the supplementary information, that APP x CysC-/- mice show a tendency toward decreased Aβ plaque accumulation, while CAA is up severalfold in these mice. Unfortunately, it appears Gan and colleagues only looked at the plaques and thus may have missed an increase in CAA and maybe total Aβ. Third, it is not clear to us why the Aβ-immunoreactive plaque load but not the thioflavin S-positive one is decreased in APP-J20 CysC-/- mice in Figure 2, while the plaque load is increased by 50 percent on a CatB-null background in Figure 6 (although this increase was not significant). Fourth, Li Gan and colleagues thus far report results only in one mouse model (APP-J20), and therefore the results may be specific to this mouse model, whereas the direct interference of CysC with Aβ amyloidosis on the other hand was reproducible in several different double transgenic mouse models. Thus, it would be nice to see the interesting results of Li Gan replicated in another mouse model.
References:
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.
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.
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