Styren S D, Kamboh M I, DeKosky S T
Department of Psychiatry, Western Psychiatric Institute and Clinic and Graduate School of Public Health, University of Pittsburgh, Pennsylvania 15261, USA.
J Comp Neurol. 1998 Jul 13;396(4):511-20.
A variety of factors and processes have been implicated in the development and progression of the pathology of Alzheimer's Disease (AD), including amyloid fragment deposition, reactive gliosis, alpha-1-antichymotrypsin (ACT), and apolipoprotein E (APOE). Carriers of the APOE 4 allele have been shown to have an enhanced risk of developing AD, and the ACT signal peptide A/A genotype may modify the APOEepsilon4 risk. The protein products of these genes have been shown to enhance conversion of diffuse beta amyloid (Abeta) fibrils, which are found in diffuse plaques, to the fibrillar form found in neuritic plaques. In affected regions of AD brain, ACT and APOE colocalize with Abeta deposits and reactive microglia and astrocytes. We examined the regional distribution of ACT, APOE, and reactive glia in temporal cortex, where neuritic plaques are abundant, and cerebellum (in areas where diffuse plaques but not neuritic plaques accumulate) to examine the relationship of these markers to the deposition of Abeta. In temporal cortex, ACT and APOE staining was localized to plaque-like profiles, reactive astrocytes, and blood vessels; human leukocyte antigen-DR (HLA-DR) and glial fibrillary acidic protein (GFAP) staining revealed focal clusters of reactive microglia and astrocytes. In cerebellum, ACT and APOE immunoreactivity was never localized to plaque-like profiles but was weakly localized to unreactive astrocytes; weak HLA-DR and GFAP immunoreactivity was present on quiescent microglia throughout the cerebellum. The lack of fibrillar amyloid deposits in cerebellum, despite the presence of well-characterized markers thought to mediate the production of Abeta, suggests that this brain region may be lacking certain factors necessary for fibril formation or that the cerebellum responds differently to stimuli that successfully mediate inflammation in affected cortex.
多种因素和过程与阿尔茨海默病（AD）病理的发生和发展有关，包括淀粉样蛋白片段沉积、反应性胶质增生、α-1抗糜蛋白酶（ACT）和载脂蛋白E（APOE）。已证明APOE 4等位基因携带者患AD的风险增加，且ACT信号肽A/A基因型可能改变APOEε4的风险。这些基因的蛋白质产物已被证明可增强弥漫性β淀粉样蛋白（Aβ）纤维（存在于弥漫性斑块中）向神经炎性斑块中发现的纤维状形式的转化。在AD脑的受累区域，ACT和APOE与Aβ沉积物以及反应性小胶质细胞和星形胶质细胞共定位。我们检查了颞叶皮质（神经炎性斑块丰富）和小脑（弥漫性斑块而非神经炎性斑块积聚的区域）中ACT、APOE和反应性胶质细胞的区域分布，以研究这些标志物与Aβ沉积的关系。在颞叶皮质中，ACT和APOE染色定位于斑块样结构、反应性星形胶质细胞和血管；人类白细胞抗原-DR（HLA-DR）和胶质纤维酸性蛋白（GFAP）染色显示反应性小胶质细胞和星形胶质细胞的局灶性簇集。在小脑中，ACT和APOE免疫反应性从未定位于斑块样结构，而是弱定位于无反应性的星形胶质细胞；整个小脑中静止的小胶质细胞上存在弱HLA-DR和GFAP免疫反应性。尽管存在被认为介导Aβ产生的特征明确的标志物，但小脑中缺乏纤维状淀粉样蛋白沉积物，这表明该脑区可能缺乏纤维形成所需的某些因素，或者小脑对成功介导受累皮质炎症的刺激反应不同。
