Caputo C B, Salama A I
Department of Pharmacology, ICI Pharmaceuticals Group, ICI Americas Inc., Wilmington, DE 19897.
Neurobiol Aging. 1989 Sep-Oct;10(5):451-61. doi: 10.1016/0197-4580(89)90096-1.
Two amyloid proteins accumulate in Alzheimer's disease. These proteins, beta amyloid protein and paired helical filament protein, are present in the hallmark lesions of Alzheimer's disease, neuritic plaques and neurofibrillary tangles. Although the amino acid sequences of these two proteins are likely to be different, they nevertheless share certain physical characteristics which define each as belonging to a common class of proteins, amyloid proteins. Since these proteins are probably important in the pathology of Alzheimer's disease, drugs that prevent their accumulation should have therapeutic utility. Based on the amyloidoses associated with other diseases, three mechanisms for amyloid formation have emerged. These mechanisms form a framework for studying Alzheimer amyloids and designing interventions. One mechanism involves posttranslational events which render a normal protein amyloidogenic. Proteolysis, phosphorylation, glycosylation, and transglutamination may be relevant posttranslational events in Alzheimer's disease. If more conclusive evidence can be generated suggesting that these events are involved in the abnormal formation of amyloid in Alzheimer's disease, then these events will become viable targets for drug therapy. Another mechanism for amyloid formation results from expression of an abnormal gene which, in the case of familial Alzheimer's disease, may be an important etiological component. A third mechanism involves the accumulation of a normal protein to a threshold concentration that spontaneously forms amyloid. An effective therapeutic approach for these last two mechanisms could likely include pharmacological manipulation of gene expression.
在阿尔茨海默病中会积累两种淀粉样蛋白。这两种蛋白，即β淀粉样蛋白和双螺旋丝蛋白，存在于阿尔茨海默病的标志性病变——神经炎性斑块和神经原纤维缠结中。尽管这两种蛋白的氨基酸序列可能不同，但它们仍具有某些物理特性，这些特性将它们各自定义为属于一类共同的蛋白——淀粉样蛋白。由于这些蛋白可能在阿尔茨海默病的病理过程中起重要作用，因此阻止它们积累的药物应该具有治疗作用。基于与其他疾病相关的淀粉样变性，已经出现了三种淀粉样蛋白形成机制。这些机制构成了研究阿尔茨海默病淀粉样蛋白和设计干预措施的框架。一种机制涉及翻译后事件，这些事件使正常蛋白具有淀粉样变性能力。蛋白水解、磷酸化、糖基化和转谷氨酰胺作用可能是阿尔茨海默病中相关的翻译后事件。如果能产生更确凿的证据表明这些事件参与了阿尔茨海默病中淀粉样蛋白的异常形成，那么这些事件将成为药物治疗的可行靶点。淀粉样蛋白形成的另一种机制是由异常基因的表达引起的，在家族性阿尔茨海默病中，该异常基因可能是一个重要的病因成分。第三种机制涉及正常蛋白积累到自发形成淀粉样蛋白的阈值浓度。针对后两种机制的有效治疗方法可能包括对基因表达进行药理学调控。
