Yang T, Li S, Xu H, Walsh DM, Selkoe DJ. Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate. J Neurosci. 2017 Jan 4;37(1):152-163. PubMed.

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  1. The experience from genetic findings in the early 1990s strongly point to Aβ as the culprit in Alzheimer’s disease. However, we still do not understand how Aβ confers cognitive dysfunctions and neuronal atrophy. For several years we have witnessed an increased interest in soluble Aβ oligomers as being the important pathogenic form of Aβ (Liu et al., 2015; Esparza et al., 2016). This paper by Yang et al. demonstrates that the predominant forms of soluble Aβ in human Alzheimer brain are higher molecular weight (HMW) oligomers. HMW oligomers eluted in the void volume of a size exclusion chromatography Superdex 75 column. The investigators then incubate these species in an alkaline buffer for 48 hours at 37°C, which leads to degradation into lower molecular weight (LMW) oligomers. The authors claim that toxicity of Aβ is mainly conferred by the small oligomers and not by the HMW oligomers, as demonstrated by effects by in vitro methods such as hippocampal LTP, activation of microglia and effect on neuronal levels of β2-adrenergic receptors.

    We have made a similar observation that the major soluble Aβ species in Alzheimer brain were HMW oligomers, but used ultracentrifugation. However, toxicity between synthetic HMW and LMW oligomers were approximately similar (Sehlin et al., 2012). By using synthetic Aβ we had previously found a fraction eluting in the void of a Superdex 75 column. This pool of oligomeric Aβ, of different sizes, we named protofibrils (Nilsberth et al., 2001). This name had been used previously (Walsh et al., 1997), and we found it appropriate to use the nomenclature of previous authors. The propensity to form protofibrils was greatly enhanced by the Arctic APP (E693G) mutation inside Aβ leading to early onset Alzheimer’s disease. We later developed an antibody against Aβ protofibrils, mAβ158 (Englund et al., 2007). The humanized version of the antibody, BAN2401, is now in a large clinical trial against Alzheimer’s disease, run by Eisai and BioArctic (Lannfelt et al., 2015). We have also used this antibody to visualize Aβ protofibrils in two AβPP-transgenic mouse models with PET (Sehlin et al., 2016), clearly demonstrating that these Aβ species are formed in vivo and are accessible to antibodies penetrating the brain.

    It is very difficult to study what is actually ongoing in the brains of Alzheimer patients. All our efforts and methods are indirect, as we at present are unable to monitor the biochemical processes that are taking place in vivo in the human brain. Thus, it is not certain that the in vitro studies used in the present paper mimic the disease processes in Alzheimer brains. Furthermore, it is unclear why the experiment was performed where the HMW material eluting in the void volume of the SEC column was subjected to degradation in alkaline conditions during 48 hours at 37°C. Is this something that reflects processes in the human Alzheimer brain? During 48 hours at 37°C many things can happen, including protease activity changing the nature of the oligomers.

    Solanezumab, a monoclonal antibody targeting the monomer of Aβ, recently failed to show clinical efficacy (see Dec 2016 conference news). However, aducanumab, an antibody with a very different Aβ-binding profile than solaneuzumab, has demonstrated a clinical effect on cognition and also reduction of Aβ plaque load as measured by amyloid PET (Sevigny et al., 2016). In contrast to solanezumab, the Aβ-binding profile of aducanumab is shifted to the “right,” i. e., toward HMW Aβ oligomers and fibrils. Sevigny et al. demonstrated that aducanumab mainly binds to Aβ fibrils and oligomers, with no monomer binding. If, as the authors suggest, the toxic effect of Aβ is caused by LMW oligomers in vivo, targeting HMW oligomers will still be beneficial since it will remove the proposed precursor of the LMW oligomers.

    With this in mind it is uncertain if the in vitro experiments in Yang et al. reflect the biochemical processes of Aβ aggregation in the brains of patients with Alzheimer’s disease. However, it is very important to understand that our scientific efforts are hampered by our lack of basic knowledge of the in vivo pathogenic processes in the human Alzheimer brain. Our conclusion is that our knowledge at present is limited, but there are certain evidences that soluble aggregated forms of Aβ are a main player in toxicity and confer neurodegeneration in Alzheimer’s disease. In previous papers some of these authors have strongly claimed that the Aβ dimer is the main cause of neurotoxicity (Shankar et al., 2008). Our position is that we do not fully understand the nature of what is killing neurons in Alzheimer’s disease, although soluble aggregated forms of Aβ are a prime suspect.

    Pär Gellerfors of BioArctic are also co-authors of this comment.

    References:

    Englund H, Sehlin D, Johansson AS, Nilsson LN, Gellerfors P, Paulie S, Lannfelt L, Pettersson FE. Sensitive ELISA detection of amyloid-beta protofibrils in biological samples. J Neurochem. 2007 Oct;103(1):334-45. PubMed.

    Esparza TJ, Wildburger NC, Jiang H, Gangolli M, Cairns NJ, Bateman RJ, Brody DL. Soluble Amyloid-beta Aggregates from Human Alzheimer's Disease Brains. Sci Rep. 2016 Dec 5;6:38187. PubMed.

    Lannfelt L, Möller C, Basun H, Osswald G, Sehlin D, Satlin A, Logovinsky V, Gellerfors P. Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease. Alzheimers Res Ther. 2014;6(2):16. Epub 2014 Mar 24 PubMed.

    Liu P, Reed MN, Kotilinek LA, Grant MK, Forster CL, Qiang W, Shapiro SL, Reichl JH, Chiang AC, Jankowsky JL, Wilmot CM, Cleary JP, Zahs KR, Ashe KH. Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration. Cell Rep. 2015 Jun 23;11(11):1760-71. Epub 2015 Jun 4 PubMed.

    Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Näslund J, Lannfelt L. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.

    Sehlin D, Englund H, Simu B, Karlsson M, Ingelsson M, Nikolajeff F, Lannfelt L, Pettersson FE. Large aggregates are the major soluble Aβ species in AD brain fractionated with density gradient ultracentrifugation. PLoS One. 2012;7(2):e32014. PubMed.

    Sehlin D, Fang XT, Cato L, Antoni G, Lannfelt L, Syvänen S. Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease. Nat Commun. 2016 Feb 19;7:10759. PubMed.

    Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6. PubMed.

    Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008 Aug;14(8):837-42. PubMed.

    Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB. Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem. 1997 Aug 29;272(35):22364-72. PubMed.

    View all comments by Linda Söderberg

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