Breaking the Code of Amyloid- Oligomers

Departing from the original postulates that defined various neurodegenerative disorders, accumulating evidence supports a major role for soluble forms of amyloid proteins as initiator toxins in Alzheimer’s disease, Parkinson’s disease, frontotemporal dementias, and prion diseases. Soluble multimeric assemblies of amyloid-β, tau, α-synuclein, and the prion protein are generally englobed under the term oligomers. Due to their biophysical properties, soluble amyloid oligomers can adopt multiple conformations and sizes that potentially confer differential biological activities. Therein lies the problem: with sporadic knowledge and limited tools to identify, characterize, and study amyloid oligomers, how can we solve the enigma of their respective role(s) in the pathogenesis of neurodegenerative disorders? To further our understanding of these devastating diseases, the code of the amyloid oligomers must be broken. 1. Commentary For a century, the cardinal features of Alzheimer’s disease (AD), amyloid plaques and neurofibrillary tangles, were thought to underlie this chronic neurological disorder. However, based on the evidence accumulated over the past ten to fifteen years, the toxicity of these lesions has been questioned. Instead, the emerging soluble aggregation-intermediate forms of amyloid-beta (Aβ) and tau proteins, which compose plaques and tangles, are now believed to underlie the synaptic and neuronal losses observed in AD. Studies focusing on oligomeric Aβ assemblies [1–4] have paved the way for other amyloid proteins including tau [5], alpha-synuclein [6–8], and the prion protein PrP [9] in the field of neurodegenerative disorders. This principle simply revolutionized our understanding of AD, Parkinson’s disease, frontotemporal dementias, and prion diseases, opening new avenues for therapeutic strategies. In what might seem like an all rosy affair, this paradigm shift also contributed to complicating even more the putative sequence of biological events responsible for these diseases. In AD, the classical view of the amyloid hypothesis postulated that amyloid plaques are altering the physiological function of neurons, which in turn disrupts tau biology leading to the demise of the cell [10]. The modern view of the amyloid hypothesis suggests the involvement of a multitude of endogenous bioactive Aβ molecules [11] that include Aβ dimers, trimers, Aβ*56, annular protofibrils, and amyloid plaques, as opposed to a single culprit (i.e., plaques). This notion appears to be consistent with the myriad cell surface receptors and signaling pathways that have