Deng A, Irizarry M C, Nitsch R M, Growdon J H, Rebeck G W
Memory Disorders Clinic and the Alzheimer's Research Unit, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Am J Pathol. 2001 Sep;159(3):1061-8. doi: 10.1016/S0002-9440(10)61781-6.
A common polymorphism in the cystatin C gene is associated with increased risk of developing Alzheimer's disease (AD). To explore possible neuropathological consequences of this genetic association, we examined expression of cystatin C in brains from 22 AD and 11 control patients by immunohistochemistry. In the temporal cortex of all AD brains, there was strong cystatin C immunostaining of neurons and activated glia, whereas staining was absent or 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 III and V, which are the neurons most susceptible to cell death in AD. The increase 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 using in situ hybridization of mouse brain. In human AD brain, there was little co-localization of cystatin C with parenchymal Abeta deposits, although a small fraction of cerebral blood vessels and neurofibrillary tangles were cystatin C-positive. The regional distribution of cystatin C neuronal immunostaining also duplicated the pattern of neuronal susceptibility in AD brains: the strongest staining was found in the entorhinal cortex, in the hippocampus, and in the temporal cortex; fewer pyramidal neurons were stained in frontal, parietal, and occipital lobes. These neuropathological observations reinforce the association between cystatin C and AD, and support a model of cystatin C involvement in the process of neuronal death in AD.
胱抑素C基因的一种常见多态性与患阿尔茨海默病（AD）的风险增加有关。为了探究这种基因关联可能产生的神经病理学后果，我们通过免疫组织化学检查了22例AD患者和11例对照患者大脑中胱抑素C的表达。在所有AD患者的颞叶皮质中，神经元和活化的胶质细胞有强烈的胱抑素C免疫染色，而在11例对照患者的大脑中，7例没有染色或染色很弱。AD患者大脑中神经元的胱抑素C染色主要局限于皮质III层和V层的锥体神经元，这些神经元是AD中最易发生细胞死亡的神经元。AD中胱抑素C染色的增加与胱抑素C基因型无关。神经元内胱抑素C的免疫染色呈点状分布，与内体/溶酶体蛋白酶组织蛋白酶B共定位。使用小鼠脑原位杂交的平行研究表明胱抑素C主要来源于胶质细胞。在人类AD大脑中，胱抑素C与实质β淀粉样蛋白沉积几乎没有共定位，尽管一小部分脑血管和神经原纤维缠结呈胱抑素C阳性。胱抑素C神经元免疫染色的区域分布也与AD大脑中神经元易感性模式一致：最强的染色出现在内嗅皮质、海马体和颞叶皮质；额叶、顶叶和枕叶中被染色的锥体神经元较少。这些神经病理学观察结果强化了胱抑素C与AD之间的关联，并支持了胱抑素C参与AD神经元死亡过程的模型。
