Numerous studies have established a pivotal role for A␤42 in Alzheimer's disease (AD) pathogenesis. In contrast, although A␤40 is the predominant form of amyloid ␤ (A␤) produced and accumulates to a variable degree in the human AD brain, its role in AD pathogenesis has not been established. It has generally been assumed that an increase in A␤40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-A␤40 mice that selectively express high levels of A␤40 with both Tg2576 (APPswe, K670NϩM671L) mice and BRI-A␤42A mice expressing A␤42 selectively and analyzed parenchymal and cerebrovascular A␤ deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of A␤40 decreased A␤ deposition by 60 -90%. These results demonstrate that A␤42 and A␤40 have opposing effects on amyloid deposition: A␤42 promotes amyloid deposition but A␤40 inhibits it. In addition, increasing A␤40 levels protected BRI-A␤40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of A␤40 with respect to amyloid deposition suggest that strategies that preferentially target A␤40 may actually worsen the disease course and that selective increases in A␤40 levels may actually reduce the risk for development of AD.

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid ␤ precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-A␤1-40 transgenes in APP mouse models. Expression of BRI2-A␤1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral A␤ deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits A␤ aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of A␤ deposition in vivo.