Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid-β oligomers

The production of amyloid-beta (A beta) is a key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of soluble A beta oligomers within the brain lead to synapse degeneration and the progressive dementia characteristic of AD. Since A beta exists in both disease-relevant (toxic) and non-toxic forms, the factors that affected the release of toxic A beta were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released A beta oligomers that caused synapse damage when incubated with cultured neurones. These A beta oligomers had similar potency to soluble A beta 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 beta, it did not cause synapse damage. The loss of toxicity was associated with a reduction in A beta oligomers and an increase in A beta monomers. The suppression of toxic A beta 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 beta. 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 beta oligomer-induced synapse damage; neuroprotection was mediated by A beta monomers. These studies support the hypothesis that the ratio of A beta monomers to A beta oligomers is a critical factor that regulates synapse damage.