Elevation of cystatin C in susceptible neurons in Alzheimer's disease

A common polymorphism in the cystatin C gene is associated with increased r isk of developing Alzheimer's disease (AD). To explore possible neuropathol ogical consequences of this genetic association, we examined expression of cystatin C in brains from 22 AD and 11 control patients by immunohistochemi stry. In the temporal cortex of aft AD brains, there was strong cystatin C immunostaining of neurons and activated glia, whereas staining was absent o r minimal in 7 of the 11 control brains. Neuronal staining of cystatin C in AD brains was primarily limited to pyramidal neurons in cortical layers II I and V, which are the neurons most susceptible to cell death in AD. The in crease in cystatin C staining in AD was independent of cystatin C genotype. Immunostaining of cystatin C within neurons showed a punctate distribution , which co-localized with the endosomal/lysosomal proteinase, cathepsin B. A primarily glial source for cystatin C was suggested by parallel studies u sing in situ hybridization of mouse brain. In human AD brain, there was lit tle co-localization of cystatin C with parenchymal A beta deposits, althoug h a small fraction of cerebral blood vessels and neurofibrillary tangles we re cystatin C-positive. The regional distribution of cystatin C neuronal im munostaining also duplicated the pattern of neuronal susceptibility in AD b rains: the strongest staining was found in the entorhinal cortex, in the hi ppocampus, and in the temporal cortex; fewer pyramidal neurons were stained in frontal, parietal, and occipital lobes. These neuropathological observa tions reinforce the association between cystatin C and AD, and support a mo del of cystatin C involvement in the process of neuronal death in AD.