Oligomers on the Brain: the Emerging Role of Soluble Protein Aggregates in Neurodegeneration.

Author(s): Dominic M. Walsh, Dennis J. Selkoe

Journal Name: Protein & Peptide Letters

Volume 11 , Issue 3 , 2004

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Extracellular fibrous amyloid deposits or intracellular inclusion bodies containing abnormal protein fibrils characterize many different neurodegenerative diseases, including Alzheimers disease (AD), Parkinsons disease (PD), dementia with Lewy bodies, multiple system atrophy, Huntingtons disease, and the transmissible ‘prion’; dementias. There is strong evidence from genetic, transgenic mouse and biochemical studies to support the idea that the accumulation of protein aggregates in the brain plays a seminal role in the pathogenesis of these diseases. How monomeric proteins ultimately convert to highly polymeric deposits is unknown. However, studies employing, synthetic, cell-derived and purified recombinant proteins suggest that amyloid proteins first come together to form soluble low n-oligomers. Further association of these oligomers results in higher molecular weight assemblies including so-called ‘protofibrils’ and ‘ADDLs’ and these eventually exceed solubility limits until, finally, they are deposited as amyloid fibrils. With particular reference to AD and PD, we review recent evidence that soluble oligomers are the principal pathogenic species that drive neuronal dysfunction.

Keywords: alzheimer, neurodegeneration, amyloid, synuclein, aggregation

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Article Details

Year: 2004
Page: [213 - 228]
Pages: 16
DOI: 10.2174/0929866043407174
Price: $65

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