Amyloid‐β Oligomers: Possible Roles as Key Neurotoxins in Alzheimer's Disease

Abstract

Alzheimer’s disease is the most common form of senile dementia. Although the amyloid-β peptide was identified in 1984 as the major constituent of the senile plaques that characterize the disease, accumulating evidence indicates that the plaque density does not correspond well to the concurrent disease state. In order to resolve this disconnect, a number of recent studies have shifted away from the senile plaque and classical fibrillar forms of amyloid toward a less well structured species as the proximate neurotoxic factor underlying cognitive failure in Alzheimer’s disease: soluble amyloid-β peptide oligomer (also known as the amyloid-β peptide–derived diffusible ligand). Paradoxically, several studies in the last 2 years have shown that picomolar levels of amyloid-β peptide have neutral activity or perhaps even an essential role in learning and memory. Here we highlight some of the key observations underlying the growing focus on the amyloid-β peptide oligomer.

Alzheimer's Disease and Prion Protein

“…It is now widely accepted that the soluble Aβ oligomers are the toxic species that leads to synaptic and cognitive dysfunction as well as neurodegeneration in AD (17,25). This concept is supported by studies showing the strong correlation of the synaptic loss with cortical levels of soluble Aβ species rather than with plaque distribution in AD patients (20,21,24), and the inhibitory effect of soluble Aβ oligomers on long-term potentiation (LTP) Figure 1.…”

“…Upon failure of all the Aβ-centric approaches that reached Phase III clinical trials, scientists began to question the pathogenic role of amyloid aggregates (senile plaques) that comprise Aβ fibrils, which is the main theme of the amyloid hypothesis (10), and speculate that Review the soluble pre-fibrillar Aβ oligomers are most likely the principal toxic forms of Aβ peptide (16)(17)(18)(19)(20). Soluble Aβ oligomers are found to be elevated in AD brains, and their levels are strongly correlated with disease onset and severity (21)(22)(23).…”

Oxidative Stress Events and Neuronal Dysfunction in Alzheimer’s Disease: Focus on APE1/Ref-1-Mediated Survival Strategies

“…But Aβ(1-42) is the main component of the amyloid deposits associated with AD and has a tendency to form aggregates spontaneously and, thus, may form oligomers. Therefore, Aβ(1-42) is considered more neurotoxic than Aβ(1-40) [ 101 ] . While both Aβ and Aβ(1-42) are capable of forming Both oligomerisation and aggregation of Aβ lead to the formation of senile plaques, a hallmark of AD phenotype.…”

Biomarkers in Alzheimer's disease

“…People with dementia living in the developing countries account for 62% of all patients, but by 2050 this will rise to 71%. The total estimated global societal direct and indirect cost of global dementia in 2010 was $604 billion [2] .…”