Hong W, Wang Z, Liu W, O'Malley TT, Jin M, Willem M, Haass C, Frosch MP, Walsh DM. Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer's disease brain. Acta Neuropathol. 2018 Jul;136(1):19-40. Epub 2018 Apr 23 PubMed.

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  1. The paper by Hong et al. represents a great step toward improving the current technology used for Aβ extraction. The authors describe a gentle method that avoids harsh homogenization by soaking human brain slices in isotonic buffer. Although the authors restricted their extraction largely to diffusible Aβ species, this did not lead to loss of Aβ to the extent one may have expected, and it still allowed the authors to perform detailed characterization of the recovered Aβ species. Remarkably, removing soluble Aβ species by soaking brain slices in isotonic buffer completely eliminated neurotoxicity [in the tissue] in the assays performed. In addition, no further active Aβ was extracted upon subsequent homogenization, even though more Aβ was released than during soaking.

    This data strongly suggests a link between Aβ toxicity and diffusible Aβ species. However, the relevance of the neurotoxicity assays used (neurite outgrowth, LTP) as well as all other in vitro Aβ toxicity assays for AD pathogenesis remains unclear and is debated. Interestingly, in size exclusion chromatography analysis, diffusible Aβ species recovered by this new method distribute widely from the low kDa into the 1,000 kDa range and show enrichment of lower molecular weight species compared to soluble Aβ extracted by homogenization. It seems likely that stronger differences occur in the even higher molecular weight range but low solubility of these species hinders analysis. Irrespective of these limitations, which are inherent to the field, this paper describes an advanced tool to enrich diffusible Aβ and provides an excellent basis for further detailed studies.

    View all comments by Christine Rother

  2. The authors of these two papers from MGH should be congratulated for further characterizing which species of Aβ oligomers may be most toxic, and for developing methods to rapidly test various antibodies for protective properties in vitro. We also wish to point out a very recent publication (Wang et al., 2018) by Brian Bacskai and collaborators at MGH and Acumen Pharmaceuticals, which describes an in vitro assay using calcium dysregulation as a measure of neuronal toxicity. They characterized antibody ACU3B3, which selectively targets subspecies of soluble Aβ oligomers and abolishes their toxic effects in primary neuronal cultures. Based in part on this emerging technology, we agree that anti-Aβ antibodies specifically or at least preferentially targeting the bioactive aggregate species may lead to effective treatments for Alzheimer’s disease. 

    Eric Siemers is consulting CMO and Franz Hefti is a board member of Acumen Pharmaceuticals, Inc., a company developing ACU193, the humanized form of antibody ACU3B3.

    References:

    Wang X, Kastanenka KV, Arbel-Ornath M, Commins C, Kuzuya A, Lariviere AJ, Krafft GA, Hefti F, Jerecic J, Bacskai BJ. An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging. Sci Rep. 2018 Mar 15;8(1):4634. PubMed.

    View all comments by Franz Hefti

  3. The article by Wong and colleagues is comprehensive and the experiments are rigorous and well-designed. The report’s main conclusion is that the pool of bioactive Aβ oligomers constitutes a minority of soluble Aβ in AD brain tissue. The results also suggest that not all pools of Aβ assemblies are neurotoxic. 

    In practical terms, these findings further support the notion that not all Aβ oligomers are equal in altering neuronal biology and function, a point our own studies have demonstrated when comparing Aβ dimers, trimers, Aβ*56, and 150kDa Aβ protofibrils purified from AD or APP transgenic mouse brains (Amar et al., 2017; Larson et al., 2012; Lesné et al., 2006; Sherman et al., 2016). The low abundance of the critical bioactive Aβ species present in the AD brain lysates is also consistent with the estimated rarity of soluble Aβ dimers, trimers, or Aβ*56 in the extracellular-enriched brain lysates generated by our group or in human cerebrospinal fluid or conditioned medium of APP transgenic neurons (Amar et al., 2017; Larson et al., 2012; Lesné et al., 2006, 2013; Sherman et al., 2016). This is particularly obvious when comparing Aβ pools present in extracellular-enriched fractions and in membrane-enriched fractions (Lesné et al., 2013; Sherman and Lesné, 2011). Further supporting these observations, the amount of each Aβ oligomer purified from brain tissue in our own studies varies between 0.5-5 ng/mg of extracellular-enriched total protein lysate (Amar et al., 2017). 

    The other major take-home message from this report is the necessity to assess the biological properties of distinct Aβ oligomers, to identify the exact Aβ assembly causing these functional alterations and to move away from synthetic Aβ mixtures. This point has crucial therapeutic repercussions because the target specificity for distinct Aβ oligomers of all Aβ antibodies recently used in clinical trials of AD (i.e., solaneuzimab, bapineuzimab, aducanumab) is unknown. Until this central information is available, it will remain challenging to fully interpret the reasons behind a failure or a success in these trials.

    References:

    Amar F, Sherman MA, Rush T, Larson M, Boyle G, Chang L, Götz J, Buisson A, Lesné SE. The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci Signal. 2017 May 9;10(478) PubMed. Expression of Concern.

    Larson M, Sherman MA, Amar F, Nuvolone M, Schneider JA, Bennett DA, Aguzzi A, Lesné SE. The complex PrP(c)-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease. J Neurosci. 2012 Nov 21;32(47):16857-71a. PubMed.

    Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. PubMed. RETRACTED

    Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH. Brain amyloid-β oligomers in ageing and Alzheimer's disease. Brain. 2013 May;136(Pt 5):1383-98. PubMed. Correction.

    Sherman MA, Lesné SE. Detecting aβ*56 oligomers in brain tissues. Methods Mol Biol. 2011;670:45-56. PubMed.

    Sherman MA, LaCroix M, Amar F, Larson ME, Forster C, Aguzzi A, Bennett DA, Ramsden M, Lesné SE. Soluble Conformers of Aβ and Tau Alter Selective Proteins Governing Axonal Transport. J Neurosci. 2016 Sep 14;36(37):9647-58. PubMed.

    View all comments by Sylvain Lesne

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