Aβ40 inhibits amyloid deposition in vivo

Numerous studies have established a pivotal role for A beta 42 in Alzheimer's disease (AD) pathogenesis. In contrast, although A beta 40 is the predominant form of amyloid beta(A beta) 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 beta 40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-A beta 40 mice that selectively express high levels of A beta 40 with both Tg2576 (APPswe, K670N + M671L) mice and BRI-A beta 42A mice expressing A beta 42 selectively and analyzed parenchymal and cerebrovascular A beta deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of A beta 40 decreased A beta deposition by 60 - 90%. These results demonstrate that A beta 42 and A beta 40 have opposing effects on amyloid deposition: A beta 42 promotes amyloid deposition but A beta 40 inhibits it. In addition, increasing A beta 40 levels protected BRI-A beta 40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of A beta 40 with respect to amyloid deposition suggest that strategies that preferentially target A beta 40 may actually worsen the disease course and that selective increases in A beta 40 levels may actually reduce the risk for development of AD.