The Toxicity and Polymorphism of β-Amyloid Oligomers

Abstract

It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment.

Development and Technical Validation of an Immunoassay for the Detection of APP669–711 (Aβ−3–40) in Biological Samples

“…Aβ is generated from the amyloid precursor protein (APP) by consecutive proteolytic cleavages executed by β- and γ-secretases [ 4 ]. Oligomeric aggregated forms of Aβ can impair synaptic function and have neurotoxic properties, and are thus believed to play a critical role in AD pathogenesis (for a recent review, see, for example, [ 5 ]). In recent years, a variety of N- and C-terminally truncated or modified versions of the canonical Aβ 1–40 and Aβ 1–42 species have been detected in amyloid plaques [ 6 , 7 , 8 ], and it appears that the exact length and amino sequence of both N- and C-termini affect aggregation tendency and neurotoxicity of the different Aβ-species [ 9 , 10 ].…”

Nanotechnology Therapy for Alzheimer′s Disease Memory Impairment Attenuation

“…The model of AD molecular mechanisms evolved in parallel with the in vitro and in vivo AD models and measuring methods, and with the development of diagnostic techniques for AD in human [ 65 , 66 , 67 ]. Initially, Aβ-PLs and NFTs were assumed to be the main driver of loss of neurites and synapses with subsequent memory impairment and dementia.…”

“…Further discoveries of AD molecular mechanisms shifted the focus from Aβ-PLs and NFTs to AβOs as the main driver of secondary tau pathology and memory impairment in AD. Consequently, the “amyloid cascade hypothesis” was revised to the “AβOs cascade hypothesis” [ 65 ]. The current consensus is that, compared to hyperphosphorylated tau and AβOs, Aβ-PLs and NFTs are less toxic, i.e., have a smaller contribution to memory impairment [ 65 , 68 ].…”

Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

“…Aβos represent a heterogeneous population of aggregation states including dimers, trimers, Aβ*56 and spherical oligomers which differ in size, morphology and cytotoxicity. They operate at different stages of the clinical progression of AD, through multiple neurotoxic mechanisms, such as receptor binding and disturbances of receptor-activated signal transduction pathway, mitochondrial dysfunction, dysregulation of Ca 2+ homeostasis, alterations of tau metabolism [73].…”