Amyloid β Modification: A Key to the Sporadic Alzheimer's Disease?

Last year marked 25 years of research into the amyloid hypothesis of Alzheimer’s disease (AD) (Selkoe and Hardy, 2016). Over the last few years, studies on this subject have provided a number of insights into the pathology of the most widespread cognitive disorder of aging; however, a successful treatment strategy has yet to be developed. The amyloid hypothesis was on the edge of being discredited due to the indistinct correlation between β-amyloid (Aβ) deposition and neuronal loss (Holmes et al., 2008; Mullane and Williams, 2013). However, recent studies have defended the Aβ peptide as a causative factor in AD and have proved it to be necessary but not sufficient to explain the pathogenesis of the disease in full (Musiek and Holtzman, 2015). An updated hypothesis suggests that, Aβ accumulation is an essential trigger that initiates a pathological cascade implicating tau protein, synuclein, and other aggregation-prone proteins. The questions still to be answered are: which events pull the trigger on the Aβ aggregation cascade and how exactly does destabilization of amyloid proteostasis promote the downstream tau pathology. The answer to the first question is clear and transparent in familial AD (fAD) as it is induced by genetic aberrations. However, it remains a mystery in so-called sporadic AD (sAD), which accounts for more than 90% of the disease cases. Currently, sporadic AD is amajor subject of study with the primary focus being, to make it “less sporadic” by finding a genetic or aging-related basis for the disease. A possible insight into the problem of sADwas found within the amyloid plaques. An analysis of plaque composition has shown that aggregated β-amyloid peptides are modified in different ways, primarily by isomerization and truncation of Aβ (Roher et al., 1993). Subsequent in vitro and in vivo studies revealed that a plethora of modifications exhibit pathogenic features; these include: increased aggregation, neurotoxicity, amyloidogenicity, and an ability to suppress long-term potentiation in the hippocampus (Shimizu et al., 2002; Kumar, 2011; Al-Hilaly et al., 2013; Kozin S. et al., 2013; Mitkevich et al., 2013; Barykin et al., 2016). Hence, we propose a model in which, aberrant post-translational modification (PTM) of the amyloid β peptide increases amyloid neurotoxicity and facilitates its aggregation thus initiating or promoting progression of sAD.