Soluble oligomers for the diagnosis of neurodegenerative diseases.

El-Agnaf, Omar M. A. and Walsh, Dominic M. and Allsop, David (2003) Soluble oligomers for the diagnosis of neurodegenerative diseases. Lancet Neurology, 2 (8). pp. 461-462. ISSN 1474-4422

Abstract

The formation of extracellular fibrous deposits of amyloid or intracellular inclusion bodies that contain abnormal protein fibrils is a common pathological feature of many neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies, multiple system atrophy, Huntington's disease, the transmissible prion dementias, and, possibly, motor-neuron disease.1 The early diagnosis of many of these diseases is problematic because of the long latency between the onset of damage to neurons in the brain and the appearance of clinical symptoms. For example, by the time PD is diagnosed, most of the dopaminergic neurons in the substantia nigra have been lost. There is no simple biochemical laboratory test that can confirm the diagnosis of any neurodegenerative disease associated with protein deposits. Genetic, transgenic, and biochemical studies suggest that accumulation of protein aggregates in the brain has a seminal role in the pathogenesis of these diseases. How monomeric proteins are converted to highly polymeric deposits is unclear, but much useful information has been obtained from the study of synthetic peptides and purified recombinant proteins. These studies suggest that amyloid proteins first coalesce to form small soluble oligomers. Further aggregation of these small oligomers produces high molecular weight assemblies—including so-called protofibrils and Aβ-derived diffusible ligands (ADDLs)—that eventually exceed solubility limits until they are deposited as amyloid fibrils. Our studies, and those of others, support the idea that soluble oligomers, rather than mature amyloid fibrils, are actually the pathogenetic species that cause neurodegeneration and neuronal death.2, 3, 4 and 5 Full-size image (24K) Soluble oligomers of synthetic Aβ peptide: pseudospheres (about 5 nm in diameter) and short curvilinear fibrils (up to 200 nm in length). Courtesy of Dominic Walsh View Within Article Recently, this hypothesis has been supported by Kayed and co-workers6 who have developed an antibody (anti-oligo) that recognises only soluble oligomeric forms of Aβ associated with AD.6 Temporal analysis of Aβ aggregation by electron microsocopy and dot blots with anti-oligo showed that the appearance of ADDLs7 and protofibrils8 and 9 was coincident with anti-oligo immuno-reactivity, which indicates that ADDLs and protofibrils share a common structural epitope. Surpisingly, anti-oligo also detects soluble oligomeric aggregates of -synuclein, islet amyloid polypeptide, polyglutamine, lysozyme, insulin, and prion protein 106–126. As with Aβ, anti-oligo did not detect the monomeric or fibrillar versions of these proteins. Thus, anti-oligo recognises a common structural epitope independent of primary protein sequence. Importantly, antioligo prevented oligomer-mediated toxicity of all the proteins tested, whereas other antibodies that were not specific for oligomers had no effect. By use of immunohistochemistry, the authors also examined the presence and distribution of soluble Aβ oligomers in the brains of patients with AD and in normal age-matched controls. Anti-oligo recognised Aβ oligomers that could not be detected by thioflavin-S in the brains of patients with AD. Furthermore, these oligomers were not detected in brain samples from normal individuals. These results support the idea that soluble oligomers of Aβ may be pathogenetic, and could also have important diagnostic implications, provided that oligomers can be detected in CSF or plasma. Support for this idea has come from recent studies where A oligomers were detected in CSF from AD patients10 and prion protein aggregates were detected in CSF from patients with Creutzfeldt-Jakob disease,11 but oligomers were not detected in control samples. Extensive clinical studies will be required to assess the validity of such procedures as potential diagnostic tests and to determine if there is any correlation between the detection of amyloid oligomers and the severity and/or stage of the disease. If oligomerisation occurs before most neurons are lost, then detection of oligomers may facilitate early diagnosis and treatment of various neurodegenerative diseases. Assays for detection of oligomers could also be used for high-throughput screening to identify small molecules that specifically bind to, and disrupt, the oligomer specific conformation. Moreover, oligomer specific assays may also be useful for the detection of proteopathies that have yet to be identified.