Elevation of cystatin C in susceptible neurons in Alzheimer's disease
Elevation of cystatin C in susceptible neurons in Alzheimer's disease
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DOI：
10.1016/s0002-9440(10)61781-6
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发表时间：
2001-09-01
影响因子：
6
通讯作者：
Rebeck, GW
中科院分区：
文献类型：
--
作者：
Deng, A;Irizarry, MC;Rebeck, GW
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。为了探索这种遗传关联可能的神经病理后果，我们通过免疫组织化学检测了22例AD患者和11例对照患者大脑中胱抑素C的表达。在阿尔茨海默病后脑颞叶皮层，神经元和活化的胶质细胞有较强的胱抑素C免疫染色，而在11个对照脑中，有7个没有或很少染色。阿尔茨海默病脑组织胱抑素C的染色主要局限于皮层III层和V层的锥体神经元，这是阿尔茨海默病中最易发生细胞死亡的神经元。AD患者胱抑素C染色升高与胱抑素C基因型无关。神经元内胱抑素C的免疫染色显示为点状分布，与内体/溶酶体蛋白酶组织蛋白酶b共定位。利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AD大脑中，尽管一小部分脑血管和神经原纤维缠结是胱抑素C阳性，但胱抑素C与实质A β沉积的共定位很少。胱抑素C神经元免疫染色的区域分布也重复了阿尔茨海默病大脑中神经元易感性的模式：内嗅皮层、海马和颞叶皮层的染色最强；额叶、顶叶和枕叶锥体神经元染色较少。这些神经病理学观察强化了胱抑素C与AD之间的联系，并支持胱抑素C参与AD神经元死亡过程的模型。
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 aft 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 A beta 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.