Amyloid-b Oligomer Specificity Mediated by the IgM Isotype – Implications for a Specific Protective Mechanism Exerted by Endogenous Auto-Antibodies Malin Lindhagen-Persson 1 , Kristoffer Bra¨ nnstro¨ m1, Monika Vestling 1 , Michael Steinitz2, Anders 1 Olofsson * 1 Department of Medical Biochemistry and Biophysics, Umea˚ University, Umea˚, Sweden, 2 Department of Pathology, Hebrew University Hadassah Medical School, Jerusalem, Israel Abstract Background: Alzheimers disease (AD) has been strongly linked to an anomalous self-assembly of the amyloid-b peptide (Ab). The correlation between clinical symptoms of AD and Ab depositions is, however, weak. Instead small and soluble Ab oligomers are suggested to exert the major pathological effects. In strong support of this notion, immunological targeting of Ab oligomers in AD mice-models shows that memory impairments can be restored without affecting the total burden of Ab deposits. Consequently a specific immunological targeting of Ab oligomers is of high therapeutic interest. Methodology/Principal Findings: Previously the generation of conformational-dependent oligomer specific anti-Ab antibodies has been described. However, to avoid the difficult task of identifying a molecular architecture only present on oligomers, we have focused on a more general approach based on the hypothesis that all oligomers expose multiple identical epitopes and therefore would have an increased binding to a multivalent receptor. Using the polyvalent IgM immunoglobulin we have developed a monoclonal anti-Ab antibody (OMAB). OMAB only demonstrates a weak interaction with Ab monomers and dimers having fast on and off-rate kinetics. However, as an effect of avidity, its interaction with Ab- oligomers results in a strong complex with an exceptionally slow off-rate. Through this mechanism a selectivity towards Ab oligomers is acquired and OMAB fully inhibits the cytotoxic effect exerted by Ab(1-42) at highly substoichiometric ratios. Anti-Ab auto-antibodies of IgM isotype are frequently present in the sera of humans. Through a screen of endogenous anti- Ab IgM auto-antibodies from a group of healthy individuals we show that all displays a preference for oligomeric Ab. Conclusions/Significance: Taken together we provide a simple and general mechanism for targeting of oligomers without the requirement of conformational-dependent epitopes. In addition, our results suggest that IgM anti-Ab auto-antibodies may exert a more specific protective mechanism in vivo than previously anticipated. Citation: Lindhagen-Persson M, Bra¨nnstro¨ m K, Vestling M, Steinitz M, Olofsson A (2010) Amyloid-b Oligomer Specificity Mediated by the IgM Isotype – Implications for a Specific Protective Mechanism Exerted by Endogenous Auto-Antibodies. PLoS ONE 5(11): e13928. doi:10.1371/journal.pone.0013928 Editor: Ashley I. Bush, Mental Health Research Institute of Victoria, Australia Received July 5, 2010; Accepted October 18, 2010; Published November 10, 2010 Copyright: 2010 Lindhagen-Persson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Ernst and Lili Rosenhain fund, Bruxelles, Belgium, J. C. Kempe, the Swedish research council, Socialstyrelsen, FAMY and the Medical Faculty of Umea˚ University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The monoclonal antibody OMAB presented in this investigation is fully own by Alexo-Tech AB (www.alexotech.com). A.O. is a shareholder of Alexo-Tech AB. Alexo-Tech AB had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript and does not in any other way interfere with the study. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: anders.olofsson@medchem.umu.se Introduction Amyloid is today linked to more than twenty-five different syndromes, of which the neurodegenerative disorder Alzheimer’s disease (AD) represents the most prominent example. Amyloid depositions in AD patients are largely composed of the Ab- peptide, derived from the proteolytic cleavage of the amyloid precursor protein (APP). Ab peptides of 39–43 residues all have clinical relevance, but Ab(1–40) and Ab(1–42) represent the most abundant variants. Ab(1–42), in particular, has a significantly higher propensity to aggregate, and has been strongly implicated in the etiology of AD [1]. Although the histopathological features of Ab depositions (plaques) are striking, the correlation between Ab depositions and the clinical symptoms of AD is weak [2]. Small and soluble Ab assemblies, known as Ab oligomers, correlate better with negative clinical status and have been suggested to be the Ab species primarily responsible for cytotoxicity. The structural features of Ab oligomers are largely unknown. Ab-targeting immunization, both passive and active, has been studied in AD mouse models and both types of immunizations have shown a dramatic improvement regarding memory and behavior [3,4,5,6,7,8]. Interestingly, passive Ab vaccination improved cognitive performance within days, without reducing plaque burden, suggesting that the removal of soluble Ab is an adequate treatment to restore cognitive function [6]. Ab and its precursor APP has both been suggested to have important roles concerning neuroprotection and neurotrophicity [9,10,11]. Therefore, to avoid interfering with the homeostatic functions of amyloid proteins, a therapeutic approach focused on clearance of Ab should preferentially target Ab oligomers while PLoS ONE | www.plosone.org 1 November 2010 | Volume 5 | Issue 11 | e13928