Soluble amyloid-β in the brain: The scarlet pimpernel

Researchers since the 1990s have predominantly focused on the amyloid hypothesis and the formation of amyloid fibrils as the culprit behind AD when we began working on soluble A beta (sA beta). Unexpectedly, this work produced several novel findings. First, we observed that N-terminal truncated peptides are the major components of soluble and insoluble A beta in AD; secondly, that all sA beta species belong to the 42 form and the sA beta x-40 species is virtually absent in AD parenchyma; thirdly, that A beta 42 in the soluble form is non-detectable by immunoblots in plaque-free, normal brains. The later observation that sA beta 42 species is present in amyloid beta protein precursor (A beta PP) over-expressing brains of patients with Down syndrome in prenatal and early postnatal development argued that sA beta is present in brain in abnormal conditions and that its appearance seeds A beta aggregation and accumulation. Although the sA beta we described in intact brain tissue appeared to match the soluble A beta oligomers detected in cell media, which were subsequently shown to be the most toxic form of A beta, our research has been virtually ignored by the Alzheimer field. It continues nevertheless. Recently we demonstrated that the sA beta species present in physiologically aging brains are different from those present in brains with sporadic AD as the latter form oligomers more quickly, are more toxic to neurons, and produce more severe membrane damage than the A beta species associated with normal brain aging. Furthermore, in familial AD, the composition of soluble A beta appears to dictate distinctive features of the disease phenotype introducing the notion of A beta strains, a concept well established in prion diseases.