Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid-ß oligomers

Nolan, W; McHale-Owen, H; Bate, C

Abstract

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

Citation

Nolan, W., McHale-Owen, H., & Bate, C. (2017). Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid-ß oligomers. Biochemical Journal, 474(17), 3045-3058. https://doi.org/10.1042/BCJ20170239

• Journal Article Type: Article
• Acceptance Date: Jul 19, 2017
• Publication Date: Aug 22, 2017
• Deposit Date: May 16, 2018
• Publicly Available Date: May 17, 2018
• Journal: BIOCHEMICAL JOURNAL
• Print ISSN: 0264-6021
• Publisher: Portland Press
• Peer Reviewed: Peer Reviewed
• Volume: 474
• Issue: 17
• Pages: 3045-3058
• DOI: https://doi.org/10.1042/BCJ20170239
• Public URL: https://rvc-repository.worktribe.com/output/1390750