Study on the mechanism of amyloid betaprotein deposition in Alzheimer's disease brain

我们从两个APP717突变的家族性阿尔茨海默病(FAD)家系(Val到Lle)和两个散发性AD脑中生化提纯了Abeta，并用质谱仪和EIA分析对其进行了表征。我们在散发性AD脑中观察到两种类型的淀粉样β蛋白，短尾型(Abeta1-40)和长尾型(Abeta1-42/43)(Mori，H.，Takio，K.，Ogawa，M.&Selkoe，D.J.，MS of Produced淀粉样β蛋白in阿尔茨海默病，J.Biol.Chem.，267：17082-17086,1992)。我们检测了FAD脑和散发性AD脑中的Abeta，发现FAD脑中Abeta的长尾形式(Abeta1-42/43)与总Abeta的比率增加。这些体内结果在体外用三种携带APP717突变的APP717基因(Val到Lle，Phe的Gly)的培养细胞得到了证实。再加上Abeta1-42/43作为“种子”的功能，增加了淀粉样原纤维形成的动力学(Jarrett，J.T.&Lansbury，P.T.Jr.(1993)Cell 73,1055-1058)，我们得出结论，APP717错义突变促进了Abeta1-42/43在脑中的积累，从而促进了从可溶性Abeta形成淀粉样原纤维的增加。这些发现提供了该FAD基因与Abeta沉积和老年斑形成的病理表型之间的因果关系。

We have biochemically purified Abeta from brains of two unrelated familial Alzheimer's disease (FAD) pedigrees with the APP717 mutation (Val to lle) and from two sporadic AD brains and characterized them by means of mass spectrometry and EIA assay. We observed two types of Abeta, the short-tail form (Abeta1-40) and the long-tail form (Abeta1-42/43) in sporadic AD brains (Mori, H., Takio, K., Ogawara, M.& Selkoe, D.J., Mass spectrometry of purified amyloid beta protein in Alzheimer's disease, J.Biol.Chem., 267 : 17082-17086,1992). We examined Abeta in FAD brains and sporadic AD brains, and found that the ratio of the long-tail form of Abeta (Abeta1-42/43) to total Abeta was increased in FAD brains. These in vivo results were confirmed in vitro using cultured cells transfected with three kinds of APP cDNAs bearing the APP717 mutations (Val to lle, Gly of Phe).Taken together with the hypothesis that Abeta1-42/43 functions as a "seed" that increases the kinetics of amyloid fibril formation (Jarrett, J.T.& Lansbury, P.T.Jr.(1993) Cell 73,1055-1058), we conclude that the APP717 missense mutation promotes the increased accumulation of Abeta1-42/43 in the brain, which results in the enhancement of amyloid fibril formation from soluble Abeta. These findings provide a causal relationship between this FAD genotype and the pathological phenotype of Abeta deposition and senile plaque fromation.