Affiliations: [a] University of Genova, Institute of Neurology, Via De Toni 5, 16132 Genova, Italy. Tel.: +39 0 10 353 7064; Fax: +39 0 10 353 8639; E-mail: mtabaton@neurologia.unige.it | [b] Case Western Reserve University, 2085 Adelbert Road, Room 419, Cleveland, Ohio 44106, USA. Tel.: +1 216 368 0587; Fax: +1 216 368 4090; E-mail: Pierluigi.Gambetti@case.edu
Abstract: 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 Aβ (sAβ). Unexpectedly, this work produced several novel findings. First, we observed that N-terminal truncated peptides are the major components of soluble and insoluble Aβ in AD; secondly, that all sAβ species belong to the 42 form and the sAβ x-40 species is virtually absent in AD parenchyma; thirdly, that Aβ42 in the soluble form is non-detectable by immunoblots in plaque-free, normal brains. The later observation that sAβ 42 species is present in amyloid β protein precursor (AβPP) over-expressing brains of patients with Down syndrome in prenatal and early postnatal development argued that sAβ is present in brain in abnormal conditions and that its appearance seeds Aβ aggregation and accumulation. Although the sAβ we described in intact brain tissue appeared to match the soluble Aβ oligomers detected in cell media, which were subsequently shown to be the most toxic form of Aβ, our research has been virtually ignored by the Alzheimer field. It continues nevertheless. Recently we demonstrated that the sAβ 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 Aβ species associated with normal brain aging. Furthermore, in familial AD, the composition of soluble Aβ appears to dictate distinctive features of the disease phenotype introducing the notion of Aβ strains, a concept well established in prion diseases.
