Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

Abstract

Abstract. An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-␤ peptide (A␤ 42 ), with intracellular flux of Ca 2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca 2+ ions induced by A␤ 42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by A␤ 42 oligomers with low solvent-exposed hydrophobicity (A−) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca 2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.

Toxic HypF-N Oligomers Selectively Bind the Plasma Membrane to Impair Cell Adhesion Capability

“…Recent research has highlighted the importance of both oligomer structure/morphology and membrane physicochemical features as key determinants of oligomer cytotoxicity, mainly arising from different timing/conditions of oligomer growth and different lipid content, respectively (13,14,18,70,71). In this context, lipid rafts have emerged as pivotal players of oligomer recruitment and cytotoxicity (18,72,73). Therefore, it is important to use new methods to describe in detail and accurately measure the affinities of different types of protein aggregates to cell membranes containing different lipid contents.…”

The acute myeloid leukemia‐associated Nucleophosmin 1 gene mutations dictate amyloidogenicity of the C‐terminal domain

“…The aggregated samples were diluted in cell culture media at a 100 μ m peptide concentration, and then added to the SH‐SY5Y cells seeded on glass coverslips for 60 min at 37 °C as previously reported . The cells were then loaded for 15 min at 37 °C with 10 μ m Fluo‐4 AM (Thermo Fisher Scientific).…”

Amyloid‐β oligomers in cellular models of Alzheimer’s disease

“…AβOs further seem to accumulate in the proximity of N‐methyl‐D‐aspartate receptor (NMDAr) or α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAr), which are fast‐acting iGluRs (Cascella et al., 2017). Hyperactivation of iGluRs causes a well‐established scenario called excitotoxicity, involving excessive intracellular load of calcium and dysfunctional downstream signaling.…”