Diffusible, highly bioactive oligomers represent a critical minority of soluble A beta in Alzheimer's disease brain

Hong, Wei; Wang, Zemin; Liu, Wen; O'Malley, Tiernan T.; Jin, Ming; Willem, Michael; Haass, Christian ; Frosch, Matthew P. und Walsh, Dominic M. (2018): Diffusible, highly bioactive oligomers represent a critical minority of soluble A beta in Alzheimer's disease brain. In: Acta Neuropathologica, Bd. 136, Nr. 1: S. 19-40

Abstract

Significant data suggest that soluble A beta oligomers play an important role in Alzheimer's disease (AD), but there is great confusion over what exactly constitutes an A beta oligomer and which oligomers are toxic. Most studies have utilized synthetic A beta peptides, but the relevance of these test tube experiments to the conditions that prevail in AD is uncertain. A few groups have studied A beta extracted from human brain, but they employed vigorous tissue homogenization which is likely to release insoluble A beta that was sequestered in plaques during life. Several studies have found such extracts to possess disease-relevant activity and considerable efforts are being made to purify and better understand the forms of A beta therein. Here, we compared the abundance of A beta in AD extracts prepared by traditional homogenization versus using a far gentler extraction, and assessed their bioactivity via real-time imaging of iPSC-derived human neurons plus the sensitive functional assay of long-term potentiation. Surprisingly, the amount of A beta retrieved by gentle extraction constituted only a small portion of that released by traditional homogenization, but this readily diffusible fraction retained all of the A beta-dependent neurotoxic activity. Thus, the bulk of A beta extractable from AD brain was innocuous, and only the small portion that was aqueously diffusible caused toxicity. This unexpected finding predicts that generic anti-oligomer therapies, including A beta antibodies now in trials, may be bound up by the large pool of inactive oligomers, whereas agents that specifically target the small pool of diffusible, bioactive A beta would be more useful. Furthermore, our results indicate that efforts to purify and target toxic A beta must employ assays of disease-relevant activity. The approaches described here should enable these efforts, and may assist the study of other disease-associated aggregation-prone proteins.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0001-6322
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198