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Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid-ß oligomers

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

Authors

W Nolan

H McHale-Owen

C Bate



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

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