br Size Stability and Toxicity A substantial

Size, Stability, and Toxicity A substantial number of investigations aiming to unravel the mechanism of the disease have accepted an intermediate structure of aggregated Aβ which is formed earlier than plaques and has been linked to the pathogenesis (Kayed and Lasagna-Reeves, 2013; Klein, 2013; Hardy and Selkoe, 2002). Despite various isoforms of Aβ, with differing propensities for aggregation, three major groups of Aβ assemblies exist. These three assemblies of Aβ are comprised of monomers, soluble oligomers, and insoluble fibrils which have been termed as ‘Aβ pools’. Each pool again encompasses multiple structures of Aβ aggregation based on various organizations (reviewed by Goure et al. (2014)). Soluble Aβ oligomers have been reported in AD to be organized into different structures ranging from dimers (Walsh et al., 2000), trimers (Walsh et al., 2000; Chen and Glabe, 2006), tetramers (Walsh et al., 2000; Chen and Glabe, 2006), pentamers and decamers (Ahmed et al., 2010), Aβ-derived diffusible ligands (ADDLs) (Hepler et al., 2006; Lambert et al., 1998), dodecamers, and Aβ*56 (Lesne et al., 2006). Toxic soluble oligomers are distinct from the monomers or higher aggregates, such as fibrils, and were identified in AD brains (Kayed et al., 2003). Based on the published data, we suggest that there is an inverse correlation between the size of Aβ assemblies and the potency of their exerted toxicity. As the size of the oligomeric assembly increases, its deleterious effects decrease (Fig. 1). Aβ dimers have been shown to assemble forming a more stable structure of higher molecular weight, termed protofibrils which are neurotoxic. Thus, dimeric units of Aβ have been considered to be an important entity providing the building blocks for the toxic KN-93 hydrochloride (O\'Nuallain et al., 2010; Mc Donald et al., 2015; Garzon-Rodriguez et al., 2000). On the contrary, in vivo micro-dialysis of mice that display age dependent plaque pathology did not detect the presence of the dimers at any age (Hong et al., 2011). It was also noticed that oligomers can form from secondary nucleation (Cohen et al., 2013). Recent studies have shown that there are at least 2 types of oligomers with type 1 being relatively more toxic than type 2 (Liu et al., 2015a), but there could be many more species of Aβ oligomers. Dodecamers and Aβ*56 appear to be diffuse throughout the tissue and exert toxic effects in cultures. Aβ*56 oligomers contain mainly replicates of Aβ trimers and were identified in the brains Tg2576 mice (Lesne et al., 2006). This soluble aggregate of Aβ appeared to impair memory function in these animals, irrespective of neuronal loss and led to synaptic dysfunction in humans (Lesne et al., 2013; Lesne et al., 2006; Lesné et al., 2008). Consistent with its toxic effects, these Aβ*56 oligomers were also found to correlate with markers of synapse dysfunction and levels of hyperphosphorylated tau (Zahs and Ashe, 2013). This suggests that toxicity is dependent on the size, aggregation state, and diffusion of Aβ oligomers. However, while Aβ*56 has been shown to be toxic it has not been compared to other oligomers for relative toxicity. It is important to identify these toxic oligomers and determine which are the most pathologically relevant to disease in order to target the most potent oligomers in treatment. The role of different cleavage variants, Aβ1–40 and Aβ1–42, has been under investigation for some time. They are the 2 dominant Aβ peptides produced by β-secretase and γ-secretase. In vitro, Aβ1–40 tends to be more stable in isolation and remains in the monomer stage longer before it aggregates to form fibrils. The authors also found that Aβ1–42 tends to remain in a mix of monomer, trimer, and tetramer until it aggregates into fibrils (Chang and Chen, 2014). It is notable that when the study mixed Aβ1–40 and Aβ1–42 in equimolar ratio the oligomers that formed were spherical and were the most toxic oligomers when applied to culture (Chang and Chen, 2014). Another group confirmed and extended these findings by applying Aβ1–40, Aβ1–42, and mixed Aβ oligomers onto cultured neurons and observed that the mixed Aβ1–40 and Aβ1–42 formed smaller oligomers on neurites than either pure peptide alone and that larger aggregates were observed in vitro on glass slides suggesting that the aggregation pathway is different in cell free applications versus culture (Johnson et al., 2013). These findings and others like them suggest an important role for the ratio of Aβ1–42 to Aβ1–40 in toxicity and that they interact to produce smaller, more stable, and more toxic structures. Since Aβ1–42 to Aβ1–40 ratio is known to be elevated in familial AD it could prove to be relevant in therapeutic interventions. Our laboratory recently developed and characterized a new antibody known as VIA which recognizes only Aβ1–42 oligomers. This antibody does not bind monomeric or fibrillar Aβ1–42 or any form of Aβ1–40. VIA has applications in helping us elucidate the role of Aβ1–42 oligomers in disease pathogenesis and may have potential as an immunotherapy (Bodani et al., 2015). Studies like these also suggest that Aβ oligomers form different strains, or structures depending on the specific length of the Aβ peptide and how it folds.