Beta-Amyloid oligomeric and monomeric states: implications for Alzheimer's Disease

Abstract

Alzheimer's Disease (AD) is by far the most common cause of dementia affecting more than 35 million people worldwide. Despite considerable research, there is still no cure for this neurodegenerative disease and available treatments are only symptomatic. In the controversial literature about AD, a predominant idea refers to the crucial role of amyloid-beta protein (Abeta) in the pathogenesis of the disease; in fact, the feature in the brain of AD patients is the presence of extracellular plaques mainly composed of Abeta. Nevertheless, Abeta is physiologically produced in healthy individuals. Due to its biophysical properties, under certain conditions, Abeta may self-aggregate into multiple forms, ranging from 4 kDa monomers and including higher-order oligomers, protofibrils, and mature fibrils. For many years, the fibrillar Abeta assemblies, similar to what seen in amyloid plaques, have been considered mainly responsible for neurodegenation associated with AD. However, the quantity and temporal progression of amyloid plaques do not correlate well with the clinical evolution of the disease. There is now extensive evidence that soluble Abeta oligomers disrupt synaptic transmission and plasticity in AD. Moreover, new studies strengthen evidence that people with sporadic AD make normal amounts of Abeta, and that the toxic buildup is due to altered peptide disposal. These data are in line with the finding previously reported by our group that Abeta in its non-toxic monomeric state has a broad neuroprotective effect in vitro. This effect depends on the stimulation of type-1 insulin-like growth factor (IGF-I) receptors and/or other receptors of the insulin superfamily. The aim of this PhD thesis was to decipher Abeta activities, focusing on the relationship between the structure/aggregation state and the neurotoxic/biological activity. In paper I we have addressed the issue of Abeta toxicity, whereas the properties of the non-toxic form of Abeta, the monomer, have been considered in paper II and III. In paper I, the neurotoxic activity of Abeta was investigated in a particular model in which anabolic-androgenic steroid (AAS) sensitize neurons to the toxicity of Abeta oligomers. We found that, concentrations of the AAS that were not neurotoxic by themselves were able to increase neuronal susceptibility to the apoptotic stimulus provided by Abeta. In paper II and III, we have demonstrated that the Abeta, in its non-toxic monomeric state, activates type I IGF receptors and mimics the metabolic actions of IGFs in neurons and peripheral cells. In neurons, endogenous Abetarelease was required to uphold glucose uptake during activation, and exogenously added Abeta monomers caused the translocation of type-3 glucose transporters to the plasma membrane with ensuing glucose uptake. We suggest that pathological aggregation of Abetamonomers, as occurring in AD, might impair neuronal ability to cope with transient needs in energy provision.