Aβ42 is essential for parenchymal and vascular amyloid deposition in mice

Considerable circumstantial evidence suggests that A beta 42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for A beta 42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express A beta 1-40 or A beta 1-42 in the absence of human amylold 0 protein precursor (APP) overexpression. Mice expressing high levels of A beta 1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of A beta 1-42 accumulate insoluble A beta 1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse A beta deposits. When mice expressing A beta 1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that A beta 1-42 is essential for amyloid deposition in the parenchyma and also in vessels.