Velazquez P, Cribbs D H, Poulos T L, Tenner A J
Department of Molecular Biology and Biochemistry, University of California, Irvine 92697, USA.
Nat Med. 1997 Jan;3(1):77-9. doi: 10.1038/nm0197-77.
Fibrillar amyloid beta-protein has been implicated in the pathogenesis of Alzheimer's disease because of its neurotoxicity and its ability to activate complement. Reactive microglia, astrocytes and complement (C') components (reviewed in ref. 6) are associated with senile plaques, the fibrillar, beta-sheet assemblies of amyloid beta-peptide found predominantly in brain from individuals with AD (ref. 7). These indications of inflammatory events are not prevalent in the nonfibrillar "diffuse" plaques often seen in age-matched control cases without dementia. Clinical studies over the past several years have correlated the use of anti-inflammatory drugs with a decrease in the incidence and progression of AD dementia and/or dysfunction, supporting a role for gliosis and inflammation in AD pathogenesis (reviewed in ref. 6). C5a, a product of C' activation, is chemotactic for microglia. Thus, complement activation provides a specific mechanism for recruiting reactive glial cells to the site of the fibrillar amyloid beta-protein plaque, which could lead to inflammatory events, neuronal dysfunction and degeneration. With the use of truncated amyloid beta-peptides, the region of amyloid beta-protein limited by residues 4 and 11 has been identified as critical in the interaction between amyloid beta-protein and C1q, the recognition component of the classical complement pathway (CCP), which results in the activation of C'. Furthermore, substitution of an isoaspartic acid for aspartic acid at amyloid beta-protein residue 7 resulted in the complete elimination of CCP-activating activity. A molecular model of this interaction has been generated that should be useful in the design of candidate therapeutic inhibitors of CCP activation by amyloid beta-protein.
纤维状β-淀粉样蛋白因其神经毒性和激活补体的能力而被认为与阿尔茨海默病的发病机制有关。反应性小胶质细胞、星形胶质细胞和补体（C'）成分（参考文献6中有综述）与老年斑相关，老年斑是主要在阿尔茨海默病患者大脑中发现的β-淀粉样肽的纤维状β折叠聚集体（参考文献7）。在无痴呆的年龄匹配对照病例中常见的非纤维状“弥漫性”斑块中，这些炎症事件的迹象并不普遍。过去几年的临床研究表明，使用抗炎药物与阿尔茨海默病痴呆和/或功能障碍的发病率及进展降低相关，这支持了胶质增生和炎症在阿尔茨海默病发病机制中的作用（参考文献6中有综述）。C5a是C'激活的产物，对小胶质细胞具有趋化作用。因此，补体激活为将反应性胶质细胞募集到纤维状β-淀粉样蛋白斑块部位提供了一种特定机制，这可能导致炎症事件、神经元功能障碍和退化。使用截短的β-淀粉样肽时，β-淀粉样蛋白中由4号和11号残基限定的区域已被确定为β-淀粉样蛋白与C1q（经典补体途径（CCP）的识别成分）相互作用的关键区域，这种相互作用会导致C'的激活。此外，在β-淀粉样蛋白7号残基处用异天冬氨酸替代天冬氨酸会导致CCP激活活性完全消除。已经构建了这种相互作用的分子模型，该模型应有助于设计β-淀粉样蛋白激活CCP的候选治疗抑制剂。
