Amyloid β oligomers (AβOs) in Alzheimer’s disease

Abstract

The causative role of amyloid β 1-42 (Aβ42) aggregation in the pathogenesis of Alzheimer's disease (AD) has been under debate for over 25 years. Primarily, scientific efforts have focused on the dyshomeostasis between production and clearance of Aβ42. This imbalance may result from mutations either in genes for the substrate, i.e., amyloid precursor protein or in genes encoding presenilin, the enzyme of the reaction that generates Aβ42. Currently, it is supposed that soluble oligomers of amyloid beta (AβOs) and not fibrillar Aβ42 within neuritic plaques may be the toxic factors acting on a very early stage of AD, perhaps even initiating pathological cascade. For example, soluble AβOs isolated from AD patients' brains reduced number of synapses, inhibited long-term potentiation, and enhanced long-term synaptic depression in brain regions responsible for memory in animal models of AD. Concentrations of AβOs in the cerebrospinal fluid (CSF) of AD patients are often reported higher than in non-demented controls, and show a negative correlation with mini-mental state examination scores. Furthermore, increased Aβ42/oligomer ratio in the CSF of AD/MCI patients indicated that the presence of soluble AβOs in CSF may be linked to lowering of natively measured monomeric Aβ42 by epitopes masking, and hence, concentrations of AβOs in the CSF are postulated to as useful AD biomarkers.

Sex‐biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi‐omic analysis

“…However, it has been shown Aβ can self‐organize into soluble oligomers in very early stages of AD pathology even in the absence of plaques. The abundance of these oligomers is negatively correlated with synapse number and cognition in both animal models of AD and patients (Mroczko, Groblewska, Litman‐Zawadzka, Kornhuber, & Lewczuk, ). Therefore, it is likely that the perturbation of Mpeg1 and other transcripts altered at this time point are in direct response to the detrimental effects of Aβ, even in the reported absence of substantial Aβ plaque deposition.…”

Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity

“…In particular, we observed that aminopyrine protects cells from amyloid Aβ42 proteotoxicity. Aβ42 is the major amyloid component in the neuritic plaques of the affected brain, playing a crucial role in the associated neurobehavioral impairments in AD . For this reason, exogenous Aβ preparations, are widely used in prototypic in vitro experimental models for AD .…”

“…Aβ42 is the major amyloid component in the neuritic plaques of the affected brain, playing a crucial role in the associated neurobehavioral impairments in AD. [55] For this reason, exogenous Aβ preparations, are widely used in prototypic in vitro experimental models for AD. [56] Their toxic activity can be exerted either through receptor recognition and death signaling or intracellular internalization.…”

Application of Optogenetic Amyloid-β Distinguishes Between Metabolic and Physical Damage in Neurodegeneration

“…Of these, soluble Aβ 65 oligomers appear to be the main toxic species in AD (Ferreira et al 2011). For example, Aβ 66 oligomers have been shown to induce neurotoxic effects including memory loss in transgenic 67 animal models (reviewed in (Mroczko et al 2018)). These studies, however, mostly rely on 68 in vitro injection of synthetic Aβ oligomers or oligomers extracted from AD brains 69 (Mroczko, Groblewska et al 2018).…”

“…For example, Aβ 66 oligomers have been shown to induce neurotoxic effects including memory loss in transgenic 67 animal models (reviewed in (Mroczko et al 2018)). These studies, however, mostly rely on 68 in vitro injection of synthetic Aβ oligomers or oligomers extracted from AD brains 69 (Mroczko, Groblewska et al 2018). There is currently a lack of tools that can directly control 70…”