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Project

An analysis of the effects of Alzheimer’s disease-associated risk factors on the toxicity of Aß aggregation (FWOODYS3)

Aggregation of the Aß peptide is believed to cause Alzheimer's disease (AD). Recently, accumulating evidence has emerged to show that Aß can associate into small soluble oligomers that are highly toxic to the brain, causing synapse loss and neuronal injury. Research into the mechanisms of generation and toxic effect of these oligomers has been hampered by the transient nature of these species: Aß oligomers are too sparsely populated and short-lived to obtain structural information and to understand the molecular mechanism of their effect in the brain. The Switch Laboratory recently established a methodology to generate a stable toxic Aß oligomer pool in quite large amounts in vitro: addition of brain lipids to biologically inert mature amyloid fibrils resolubilises these fibres into stable toxic oligomers which are indistinguishable from previously identified disease-associated oligomers. This opens up the opportunity to investigate the structure-activity determinants of Aß oligomer toxicity, involved in the pathogenesis of AD, in detail. We will aim at understanding the structural determinants of oligomer toxicity using a wide array of biophysical techniques in combination with biological read-outs ranging from toxicity assays on neuronal cell cultures to behavioural studies in mice. More specifically, we will focus on protein-engineering approaches as well as other perturbation methods to analyse the aggregation mechanism and structure of toxic oligomers. In parallel we will study various natural (in-brain) effectors of Aß oligomerisation, including 40/42 ratio, membrane lipids, apolipoproteins and Tau protein. We will investigate how these factors interfere with the mechanism and stability of Aß oligomers and, hence, augment or diminish the toxic action of Aß in the brain verified by experiments on hippocampal slices, cell cultures and animal studies. Finally we will use the outcome from our study to develop therapeutic strategies. Chemical compound libraries are available in the laboratory to search for such targets.
Date:1 Jan 2009 →  31 Dec 2013
Keywords:Applied Biology
Disciplines:Biological sciences