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

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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.