Amyloid β protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain

The amyloid β protein (Aβ) deposited in the Alzheimer's disease (AD) brain is heterogeneous at both its amino and carboxyl termini. Recent studies of the genetic forms of AD indicate that the aggregation and deposition of Aβ42 may be a common initiating event in all forms of AD. Here, we analyzed the amino termini of the Aβ species deposited in the AD brain, focusing specifically on species with amino-terminal pyroglutamate at position 3 (Aβ3(pE)). Immunocyto-chemical analysis of AD brains with an antibody specific for Aβ3(pE) confirmed that these species deposit in blood vessels and senile plaques. Using specific sandwich ELISAs, we determined the amounts of Aβ3(pE)-40 and Aβ3(pE)-42(43) in AD brain compared with other fores. This analysis showed that Aβ3(pE)-40 is closely correlated with the extent of Aβ deposition in blood vessels, whereas Aβ3(pE)-42(43) is not. In addition, Aβ3(pE)-42(43) is an important component of the Aβ deposited in senile plaques of the AD brain, constituting approximately 25% of the total Aβ42(43). In vitro comparison of Aβ1-42 and Aβ3(pE)-42 showed that Aβ3(pE)-42 is highly prone to oligomerization. These findings suggest that Aβ3(pE)-42 may be particularly important in AD pathogenesis. (C) 2000 Academic Press.