While most studies support the idea for

While most studies support the idea for the use of Aβ oligomer specific pten pathway as therapeutics, there are some researchers arguing that these antibodies are still toxic and may increase the toxicity of Aβ oligomers. One study aiming to explain the meningoencephalitis seen in clinical trials looked at several antibodies which bind different forms of Aβ: Aβ1–40 and Aβ1–42 (Morkuniene et al., 2013). In the presence of microglia the antibody #11E12, in complex with either Aβ1–40 or Aβ1–42 oligomers, was more toxic than when oligomers were applied alone. The authors suggest that the microglia FcγR receptor was mediating this interaction (Morkuniene et al., 2013). However, it is important to note that the antibody used in this study recognized the N-terminal which has been shown to increase toxicity by disaggregating fibrillar Aβ into oligomers and they did not investigate other antibodies that recognize the C-terminal or middle sections of Aβ. The use of N-terminal antibodies could be disastrous if these mechanisms act synergistically by increasing oligomer and antibody–antigen complex concentration and increasing oligomer concentration through the disaggregation of fibrillar Aβ. However, there is another potential reason for the increased toxicity of these antibodies when complexed with oligomers. The peripheral sink hypothesis states that the antibody–antigen complex may be cleared from the brain through the blood creating a decrease, or sink, in the Aβ levels in the brain. This mechanism of clearance cannot be tested in culture since the Aβ-antibody complex remains in the media. To test these concepts, it would be interesting to see if these results can be validated in vivo through the use of microglia suppressors as well as investigating the peripheral sink hypothesis through serum analysis. Further research into immunotherapies is warranted with an emphasis on oligomer specific antibodies but many obstacles remain. Immunotherapy studies need to start including inflammation markers to better predict complications in humans. Antibodies targeting a region of the peptide sequence are not proving to be effective and cross react with too many forms of Aβ. Perhaps conformational antibodies are the key to targeting the oligomers specifically. It was suggested several years ago that the sequence may not be as important as the conformation in producing toxicity. A generic amyloid oligomer antibody proved effective at reducing plaque burden with decreased microhemorrhaging (Rasool et al., 2012). It is important to point out that this antibody selectively recognized oligomers but did not differentiate between amyloid proteins such as Aβ and tau. Rasool et al. (2012) also conducted active immunization prior to the appearance of plaques in the Tg2576 mouse model and the random sequence oligomer antigen produced less autoimmune response than active immunization with Aβ. The random sequence oligomer antigen was made from a random 20mer sequence of 8 amino acids, had low homology to human proteins, and strongly reacted with A11 oligomer specific antibody (Rasool et al., 2012). This study was followed by a report that monoclonal amyloid oligomer antibodies, made from this random sequence oligomer antigen, administered by passive immunization reduced plaque burden, reduced hyperphosphorylated tau, and improved cognition in 3xTg-AD mice (Rasool et al., 2013). To our knowledge, these studies have not been extended further in the last few years but warrant further investigation due to their efficacy and decreased inflammatory responses. Passive immunotherapy targeting oligomeric conformations is still the most promising avenue towards treating AD. Targeting toxic oligomers from different proteins with a single antibody which recognizes conformational similarities would likely be therapeutically beneficial since many disease including AD are characterized by aggregates of multiple proteins (Guerrero-Munoz et al., 2014a; Rasool et al., 2013; Kayed and Glabe, 2006; Kayed et al., 2003; Kayed and Lasagna-Reeves, 2013). Oligomer specific immunotherapy is proving to be effective in rodent and culture studies but needs to be extended into clinical trials.