Studies on beta-amyloidogenesis-isolation of membrane-bound Abeta

在A β的羧基末端的两个残基的差异，一个终止于瓦尔-40（A β 40），另一个终止于Ala-42（A β 42），最近被强调为参与β-淀粉样蛋白生成的重要因素。利用特异性识别A β 40和A β 42的末端特异性单克隆抗体，它们的水平已经通过EIA在一般人群和AD患者的软脑膜和皮层中灵敏地定量。众所周知，软脑膜中的薄脑膜血管是A β沉积的部位，称为脑淀粉样血管病（CAA）。EIA结果清楚地表明：（i）在一般人群中，Abeta水平在50-70岁期间急剧增加;（ii）Abeta 42水平几乎总是比Abeta 40高几倍，并且存在CAA为Abeta 42阳性，但Abeta 40阴性的阶段;以及（iii）在AD患者的软脑膜中，Abeta 40水平远高于Abeta 42。类似地，对一般人群和AD患者的枕颞皮质和CA 1中的Abeta水平进行定量，发现在50-70岁期间急剧增加。A β 40水平的升高是伴随着A β 42水平的升高而升高的，因此，有理由推测A β代谢的急性中断是AD发生的第一步，老年斑和脑淀粉样血管病的形成可能是A β代谢急性中断的结果。

A two-residue difference in the carboxyl terminus of Abeta, one terminating at Val-40 (Abeta40) and the other terminating at Ala-42 (Abeta42) , has recently been highlighted as an important factor involved in beta-amyloidogenesis. With end-specific monoclonal antibodies that specifically recognize Abeta40 and Abeta42, their levels have been sensitively quantitated by EIA in the leptomeninges and cotices in the general population and AD patients.Leptomeniongeal vessels in the leptomeninges are well known to be the site for Abeta deposition, called cerebral amyloid angiopathy (CAA). The EIA results have clearly shown that (i) Abeta levels steeply increase during the age of 50-70 in the general population ; (ii) Abeta42 level is almost always several-fold higher than that of Abeta40 and there is a stage where CAA is Abeta42-positive, but Abeta40-negative ; and (iii) Abeta40 level is much higher than Abeta42 in the leptomeninges from AD patients. Similarly, Abeta levels in occipitotemporal cortex and CA1 in the general population and AD patients were quantitated and found to increase steeply during the age of 50-70. Apparently, increases in Abeta40 level followed increases in Abeta42 level.It is reasonable to speculate that this acute disruption of Abeta metabolism is the very first step to AD.Thus, the formation of senile plaque and cerebral amyloid angiopathy is presumably the consequence of the acute disruption of Abeta metabolism.