Distinct types of amyloid‐β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease

Abstract

Soluble oligomers of amyloid-β (Aβ) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of Aβ oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble Aβ oligomers based on their morphology, size, and structural reactivity toward the conformationspecific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble Aβ oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for Aβ oligomers such as N-methyl-D-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of Aβ oligomers with the lipid membranes; (iii) intraneuronal accumulation of Aβ by α7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncover potential targets for designing AD therapeutics.

In Vivo Near-Infrared Fluorescence Imaging Selective for Soluble Amyloid β Aggregates Using y-Shaped BODIPY Derivative

“…Moreover, many reports indicated that the amount of soluble Aβ aggregates correlated much better with the severity of cognitive deficits than that of Aβ fibrils. − Therefore, soluble Aβ aggregates are increasingly drawing attention as the therapeutic target , and a novel biomarker of AD. However, because soluble Aβ aggregates are diverse and transient, , the most toxic form of soluble Aβ aggregates is controversial, , and various toxic forms of soluble Aβ aggregates may exist in AD brains at the same time. , Hence, it is expected that the development of imaging probes for simultaneous in vivo detection of diverse soluble Aβ aggregates will contribute to the elucidation of the pathophysiology of AD, assessment of therapeutic agents for AD, and accurate diagnosis of AD in the early phase.…”

ALaSCA: a computational platform for quantifying the effect of proteins using Pearlian causal inference, with an example application in Alzheimer’s disease

“…Indeed, in early Alzheimer’s disease human samples and in an amyloid precursor protein mouse model, it has been shown that the expression of orthologs of fz (FZD1 and FZD7) in the hippocampus was altered (Palomer et al ., 2022). The fz receptors were also implicated in the mechanism whereby soluble Aβ oligomers resulted in cognitive decline (Madhu et al ., 2021).…”

Two new alkaloids from Dendrobium nobile Lindl. exhibited neuroprotective activity, and dendrobine alleviated Aβ1−42‐induced apoptosis by inhibiting CDK5 activation in PC12 cells

“…Aβ oligomers cause apoptosis, which finally results in neuronal death (Madhu & Mukhopadhyay, 2021). Therefore, prevention of neuronal apoptosis is considered to be a therapeutic strategy for AD.…”

“…In AD brains, Aβ monomers aggregate into oligomers, protofibrils, and insoluble amyloid fibrils (Michaels et al, 2020). Soluble Aβ oligomers exert deleterious effects in AD, and Aβ 42 oligomers are considered especially neurotoxic (Madhu & Mukhopadhyay, 2021). The NMDAR antagonist memantine, at proper concentration, preferentially blocks pathologically‐stimulated extrasynaptic NMDARs over physiologically‐activated synaptic NMDARs, and partially ameliorates Aβ‐induced synaptic toxicity and cognitive deficit (Tu et al, 2014).…”