For a considerable period of

For a considerable period of time, research in the AD field mainly encompassed the study of senile plaques composed primarily of Aβ which is one of the characteristic hallmarks of AD and explained by an earlier version of the amyloid cascade hypothesis. It relied on the fact that Aβ is released in the extracellular space where it accumulates into senile plaques leading to the formation of neurofibrillary tangles of tau protein and causing vascular damage, cell loss, and dementia (Hardy and Higgins, 1992). But researchers were intrigued by the lack of correlation between the manifestation of the disease and the plaque burden. Neuronal death also occurred in brain regions devoid of plaques. It was then discovered that Aβ plaques were present in cognitively normal individuals (Erten-Lyons et al., 2009; Sloane et al., 1997). The existence of non-demented individuals with advanced AD neuropathology demonstrates that plaque burden does not correspond to cognition or degeneration. These individuals had significant plaque burden but no memory impairments or changes in brain volume (Erten-Lyons et al., 2009). Larger insoluble aggregates, such as Aβ plaques, did not induce memory impairment in the absence of oligomers in Tg2576 mice that develop plaque pathology and behavioral deficits at 9–10months old. In fact, a reduction in oligomer levels corresponded to improved memory in these mice (Lesné et al., 2008; Hsiao et al., 1996). Soluble Aβ oligomers, on the other hand, have been shown to produce cognitive deficits in the absence of plaques (Gandy et al., 2010). Moreover, there are individuals who appear to have AD but show no pathological changes in their brains demonstrating that larger lpa receptor are not essential to cognitive impairment (Petersen et al., 2013). These results suggest that larger aggregates are not responsible for neurodegeneration and that the smaller soluble oligomers are the toxic species of Aβ. It was then that the focus of research shifted to an alternate entity, soluble oligomers of Aβ. Electron microscopy and atomic force microscopy revealed that the toxic soluble oligomers are spherical in shape ranging from about 3 to 10nm. These spheroidal structures come together forming strings of beads, termed as protofibrils which also possess toxic effects (Glabe, 2006). In addition, Aβ1–42 protofibrils but not fibrils were shown to stimulate microglial production of tumor necrosis factor α suggesting a role for soluble Aβ aggregates in stimulating inflammatory responses and toxicity (Paranjape et al., 2012). Oligomers of different proteins were reported to take a common sequence-independent conformation which suggests that a similar mechanism of toxicity would exist for all the amyloid diseases (Kayed and Glabe, 2006; Chiti and Dobson, 2006; Campioni et al., 2010). Aβ oligomers exert their toxicity through a variety of mechanisms including receptor and direct membrane interactions, reviewed by Kayed and Lasagna-Reeves (2013). At the same time, many amyloidogenic proteins, such as tau and α-synuclein (α-syn), also shifted from larger aggregates to oligomers as the toxic species suggesting a universal mechanism of toxicity for amyloid proteins such as tau (Gerson and Kayed, 2013), α-syn (Sengupta et al., 2015), and TAR DNA-binding protein 43 (TDP-43) (Choksi et al., 2014; Fang et al., 2014). We have previously demonstrated that apart from their individual oligomeric assemblies, different pathogenic proteins also co-aggregate or form hybrid oligomers including tau with α-syn and TDP-43 with Aβ, α-syn, and cellular prion protein (PrPc) in AD patients (Sengupta et al., 2015; Guerrero-Munoz et al., 2014b). For the purpose of this review we define oligomers as trimers of Aβ or larger with a conformation distinct from fibrils. In this review we will discuss oligomer size and conformation in relation to the current literature on toxicity, inflammation, and immunotherapy with a focus on Aβ but extending to other amyloid oligomers where the mechanisms seem universal. We will emphasize the role of spreading oligomers in the progression of AD.