The amyloid proteins of Alzheimer's disease as potential targets for drug therapy.
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.
Caputo
C B
CB
Department of Pharmacology, ICI Pharmaceuticals Group, ICI Americas Inc., Wilmington, DE 19897.
Salama
A I
AI
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides; D003599:Cytoskeleton / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational
D000682:Amyloid; D016229:Amyloid beta-Peptides