Soluble amyloid-beta in the brain: the scarlet pimpernel

Topic: Brain proteins, microglia and lab models

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 Abeta (sAbeta). Unexpectedly, this work produced several novel findings. First, we observed that N-terminal truncated peptides are the major components of soluble and insoluble Abeta in AD; secondly, that all sAbeta species belong to the 42 form and the sAbeta x-40 species is virtually absent in AD parenchyma; thirdly, that Abeta42 in the soluble form is non-detectable by immunoblots in plaque-free, normal brains. The later observation that sAbeta 42 species is present in amyloid beta protein precursor (AbetaPP) over-expressing brains of patients with Down syndrome in prenatal and early postnatal development argued that sAbeta is present in brain in abnormal conditions and that its appearance seeds Abeta aggregation and accumulation. Although the sAbeta we described in intact brain tissue appeared to match the soluble Abeta oligomers detected in cell media, which were subsequently shown to be the most toxic form of Abeta, our research has been virtually ignored by the Alzheimer field. It continues nevertheless. Recently we demonstrated that the sAbeta 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 Abeta species associated with normal brain aging. Furthermore, in familial AD, the composition of soluble Abeta appears to dictate distinctive features of the disease phenotype introducing the notion of Abeta strains, a concept well established in prion diseases.

@article{tabaton2006-16914851,
  author  = {Tabaton, M. and Gambetti, P.},
  title   = {{Soluble amyloid-beta in the brain: the scarlet pimpernel}},
  journal = {Journal of Alzheimer's disease : JAD},
  year    = {2006},
  doi     = {10.3233/jad-2006-9s315},
  pmid    = {16914851},
  url     = {https://doi.org/10.3233/jad-2006-9s315}
}

Key findings

• First, we observed that N-terminal truncated peptides are the major components of soluble and insoluble Abeta in AD; secondly, that all sAbeta species belong to the 42 form and the sAbeta x-40 species is virtually absent in AD parenchyma; thirdly, that Abeta42 in the soluble form is non-detectable by immunoblots in plaque-free, normal brains.
• Recently we demonstrated that the sAbeta 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 Abeta species associated with normal brain aging.

Why it matters

This paper reports that N-terminal truncated peptides are the major components of soluble and insoluble amyloid beta in Alzheimer disease, that soluble amyloid beta species belong to the 42 form, and that soluble amyloid beta 42 is present in Down syndrome brains in prenatal and early postnatal development. It describes research findings about amyloid beta forms and reports no treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.3233/jad-2006-9s315
• PubMed: 16914851
• Original source →

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