It is interesting to note that most of the

It is interesting to note that most of the current research indicates that Aβ oligomers are inducing inflammation through several receptors such as RAGE, Toll-like receptors, nod-like receptors, and formyl peptide receptors (Minter et al., 2015; He et al., 2012) but there are still conflicting reports on which strain of Aβ is inducing the inflammation (Ferrera et al., 2014). Inflammation appears prior to the formation of larger glibenclamide cost suggesting that the smaller oligomers, which form first, are initiating this inflammation. Conflicting reports about Aβ fibrils or oligomers inducing inflammation could easily be the result of different methods. Studies on in vitro microglia cultures implicate Aβ fibrils (Ferrera et al., 2014) while, in vivo mouse injections implicate Aβ oligomers in causing inflammation (He et al., 2012). Or it could be the difference in acute responses versus prolonged responses in the aforementioned studies. Inflammation is one of the earliest signs of AD beginning prior to the formation of Aβ plaques as mentioned above. While there is evidence that Aβ is inducing the inflammation through many mechanisms such as receptor mediated or direct interaction with the membrane, it is still debated which came first: oligomer or inflammation. Understanding the sequence of events at this stage could provide insight into the mechanisms by which pathology spreads. For example, does chronic inflammation lead to the initial formation of Aβ oligomer seeds and the spread of pathology? Or perhaps as the Aβ oligomers spread and seed aggregation in new regions, they induce inflammation and accelerate degeneration. These questions are not only relevant for Aβ oligomers but other amyloids as well, especially tau. Tau oligomers are known to spread locally and via synaptic connections (Boluda et al., 2015; Ahmed et al., 2014; Asai et al., 2015). Since most amyloids are known to spread and propagate over the course of disease, the question of inflammation preceding amyloid oligomers or oligomers preceding inflammation is a relevant topic for all amyloidogenic proteins.
Immunotherapy Removing plaques from the brains of AD patients does not appear to be effective and the targeting of oligomeric forms of Aβ seems to be the most promising therapeutic in development. The mechanism by which these antibodies work is thought to be through the binding of extracellular oligomers preventing the spread of the pathology and they do not bind to plaques. These antibodies do not need to be able to get inside cells but can instead reduce or eliminate the cell to cell spread of Aβ oligomers preventing oligomers from seeding pathology in new regions or initiating inflammation. Other amyloids such as α-syn and tau are also showing reduced spreading and degeneration using immunotherapy suggesting that Aβ oligomers could be similar. Several studies support this idea that the antibodies work by binding extracellular amyloids and prevent the spread of the seeds into new regions (Valera and Masliah, 2015; Sankaranarayanan et al., 2015; Valera et al., 2015). Thus, these antibodies prevent the progression of the pathology. Another study showed that an antibody to α-syn protected cells in culture by binding to it and preventing it from entering the cell and seeding the endogenous α-syn (Tran et al., 2014). Preventing the spread of pathology could be key in treating AD. Additionally, combination therapies targeting Aβ oligomers along with inflammation or other amyloid oligomers could provide the edge that many of these therapies lack on their own. Such treatments have already been called for by the α-syn field and may apply to other amyloids such as Aβ (Valera and Masliah, 2015). Removing Aβ oligomers while inhibiting inflammation and reducing other amyloid oligomers could work synergistically by targeting key problem areas in this multifactorial disease.
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