Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid-β oligomers

Abstract

The production of amyloid-β (Aβ) is a key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of soluble Aβ oligomers within the brain lead to synapse degeneration and the progressive dementia characteristic of AD. Since Aβ exists in both disease-relevant (toxic) and non-toxic forms, the factors that affected the release of toxic Aβ were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released Aβ oligomers that caused synapse damage when incubated with cultured neurones. These Aβ oligomers had similar potency to soluble Aβ oligomers derived from the brains of Alzheimer's patients. Although the conditioned media from 7PA2 cells treated with the cellular prion protein (PrP) contained Aβ, it did not cause synapse damage. The loss of toxicity was associated with a reduction in Aβ oligomers and an increase in Aβ monomers. The suppression of toxic Aβ release was dependent on the glycosylphosphatidylinositol (GPI) anchor attached to PrP, and treatment of cells with specific GPIs alone reduced the production of toxic Aβ. The efficacy of GPIs was structure-dependent and the presence of sialic acid was critical. The conditioned medium from GPI-treated cells protected neurones against Aβ oligomer-induced synapse damage; neuroprotection was mediated by Aβ monomers. These studies support the hypothesis that the ratio of Aβ monomers to Aβ oligomers is a critical factor that regulates synapse damage.

Simple and Fast Assay for Apolipoprotein E Phenotyping and Glycotyping: Discovering Isoform-Specific Glycosylation in Plasma and Cerebrospinal Fluid

“…When apoE4 residues 166-299 were removed, the ability of apoE4 to remove A␤ was significantly decreased, resulting in intracellular A␤42 accumulation [42]. Studies of A␤ have shown that the binding to sialic acids reduces A␤ cell toxicity [43][44][45]. Taken together with the current findings that apoE4 is the least glycosylated isoform, especially in CSF, it is speculated that reduced glyco-sylation/sialylation of apoE4 could result in reduced binding to A␤, which in turn could lead to a reduced ability to remove the deposited A␤ plaques.…”