Comparison of neurotoxicity of different aggregated forms of Aβ40, Aβ42 and Aβ43 in cell cultures

Abstract

The abnormal deposition of amyloid-β (Aβ) peptides in the brain is the main neuropathological hallmark of Alzheimer's disease (AD). Amyloid deposits are formed by a heterogeneous mixture of Aβ peptides, among which the most studied are Aβ40 and Aβ42. Aβ40 is abundantly produced in the human brain, but the level of Aβ42 is remarkably increased in the brain of AD patients. Aside from Aβ40 and Aβ42, recent data have raised the possibility that Aβ43 peptides may be instrumental in AD pathogenesis. Besides its length, whether the Aβ aggregated form accounts for the neurotoxicity is also particularly controversial. Aβ fibrils are generally considered as key pathogenic substances in AD pathogenesis. Nevertheless, recent data implicated soluble Aβ oligomers as the main cause of synaptic dysfunction and memory loss in AD. To further address this uncertainty, we analyzed the neurotoxicity of different Aβ species and Aβ forms at the cellular level. The results showed that Aβ42 could form oligomers significantly faster than Aβ40 and Aβ43 and Aβ42 oligomers showed the greatest level of neurotoxicity. Regardless of the length of Aβ peptides, Aβ oligomers induced significantly higher cytotoxicity compared with the other two Aβ forms. Surprisingly, the neurotoxicity of fibrils in PC12 cells was only marginally but not significantly stronger than monomers, contrary to previous reports. Altogether, our findings demonstrate the high pathogenicity of Aβ42 among the three Aβ species and support the idea that Aβ42 oligomers contribute to the pathological events leading to neurodegeneration in AD. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Lactobacillus plantarum C29‐Fermented Soybean (DW2009) Alleviates Memory Impairment in 5XFAD Transgenic Mice by Regulating Microglia Activation and Gut Microbiota Composition

“…Oral administration of FDS or C29 also significantly suppressed the activated microglia (CD11b + /CD11c + ) population in the hippocampus and cortex of Tg mouse brains (Figure H, I). β‐ and γ‐secretases and caspase‐3 catalyze the formation of Aβ plaques, resulting in the neuronal cell death . These results suggest that FDS and C29 can suppress Aβ expression through NF‐κB activation and Aβ‐induced neuronal cell death by suppressing the expression of β‐ and γ‐secretases and caspase‐3.…”

“…Aβ is cleaved from amyloid precursor protein (APP) by β‐ and γ‐secretases . Aβ plaque is formed by full length Aβ, Aβ (1–40), and/or Aβ (1–42), which is the most toxic, and promoted by the mutation of APP and/or presenilin‐1 (Psen‐1) . Actually, several mutation sites in familial AD patients were observed .…”

Reduced Influence of apoE on Aβ43 Aggregation and Reduced Vascular Aβ43 Toxicity as Compared with Aβ40 and Aβ42

“…Increased toxicity of Aβ43, compared with Aβ40 and Aβ42, has been demonstrated in primary neurons and various cell lines, including SH-SY5Y cells, and PC12 cells [9,10,57,58]. However, not all cells may be equally sensitive towards the effects of Aβ, which is illustrated by the recent observation that Aβ42 is much more toxic towards neurons compared with glial cells [59].…”

Theory of concentric β-barrel structures: models of amyloid beta 42 oligomers, annular protofibrils, and transmembrane channels

“…Their stability has allowed the molecular structure of some forms to be determined experimentally, but even these assemblies come in multiple forms: some have U-shaped monomers 1,2 ; others have S-shaped monomers [3][4][5] , some have twofold symmetry along their long axis and others have three-fold symmetry 4,5 ; and most have parallel β-sheets, but at least one highly toxic mutant has antiparallel β-sheets 6 . However, evidence is increasing that much smaller assemblies, called oligomers, are more detrimental (reviewed in Mroczko et al, 2018 7 ) and that those formed by the longer of the two major forms, Aβ42, are the most toxic 8 .…”