Biophysical characteristics of lipid‐induced Aβ oligomers correlate to distinctive phenotypes in transgenic mice

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects cognition and memory. Recent advances have helped identify many clinical sub-types in AD. Mounting evidence point toward structural polymorphism among fibrillar aggregates of amyloid-β (Aβ) to being responsible for the phenotypes and clinical manifestations. In the emerging paradigm of polymorphism and prion-like propagation of aggregates in AD, the role of low molecular weight soluble oligomers, which are long known to be the primary toxic agents, in effecting phenotypes remains inconspicuous. In this study, we present the characterization of three soluble oligomers of Aβ42, namely 14LPOs, 16LPOs, and GM1Os with discreet biophysical and biochemical properties generated using lysophosphatidyl glycerols and GM1 gangliosides. The results indicate that the oligomers share some biophysical similarities but display distinctive differences with GM1Os. Unlike the other two, GM1Os were observed to be complexed with the lipid upon isolation. It also differs mainly in detection by conformation-sensitive dyes and conformation-specific antibodies, temperature and enzymatic stability, and in the ability to propagate morphologically-distinct fibrils. GM1Os also show distinguishable biochemical behavior with pronounced neuronal toxicity. Furthermore, all the oligomers induce cerebral amyloid angiopathy (CAA) and plaque burden in transgenic AD mice, which seems to be a consistent feature among all lipid-derived oligomers, but 16LPOs and GM1Os displayed significantly higher effect than the others. These results establish a correlation between molecular features of Aβ42 oligomers and their distinguishable effects in transgenic AD mice attuned by lipid characteristics, and therefore help bridge the knowledge gap in understanding how oligomer conformers could elicit AD phenotypes. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Ganglioside enriched phospholipid vesicles induce cooperative Aβ oligomerization and membrane disruption

“…DMPC generated oligomers had a slightly higher cytotoxicity compared to LR and TBE (Figure 3e). Overall, these data suggest that LUVs with different surface properties and charge could lead to the generation of structurally distinctive neurotoxic oligomers as observed in micellar systems 22 .…”

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

“…71 Studies have also shown that Aβ oligomers derived from fatty acids, micellar phospholipids, and GM1 build up the amyloid plaques in AD transgenic mice. 98,99 In 1993, Arispe et al 100 demonstrated that the synthetic Aβ peptide inserts into the artificial lipid bilayer and form cation-selective channels. One of the mechanisms of neurodegeneration caused by Aβ is through the amyloid pores formation.…”

“…Various neurodegenerative amyloid disorders like Parkinson's disease and AD have long been associated with increased cell permeability and increased intracellular concentration of calcium ions (Figure 3). 71 Studies have also shown that Aβ oligomers derived from fatty acids, micellar phospholipids, and GM1 build up the amyloid plaques in AD transgenic mice 98,99 . In 1993, Arispe et al 100 demonstrated that the synthetic Aβ peptide inserts into the artificial lipid bilayer and form cation‐selective channels.…”

αS oligomers generated from polyunsaturated fatty acid and dopamine metabolite differentially interact with Aβ to enhance neurotoxicity

“…Cell viability assay was carried out using 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) in SH-SY5Y cells as described in our previously established protocols [40,43]. Briefly, human neuroblastoma SH-SY5Y were maintained at 37 °C with 5.5 % CO2 in DMEM: F12 (1:1) media containing 10% FBS and 1% penicillin/streptomycin.…”

“…Circular dichroism (CD) spectra of respective samples were measured in 20 μM Tris buffer pH 8.0 in the far UV region in Jasco J-815 spectrophotometer (Jasco MD) using the established protocol [43].…”