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Monoclonal antibodies selective for α‐synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α‐synuclein transgenic mice with the disease‐causing A30P mutation
Author(s) -
Fagerqvist Therese,
Lindström Veronica,
Nordström Eva,
Lord Anna,
Tucker Stina M. E.,
Su Xingjian,
Sahlin Charlotte,
Kasrayan Alex,
Andersson Jessica,
Welander Hedvig,
Näsström Thomas,
Holmquist Mats,
Schell Heinrich,
Kahle Philipp J.,
Kalimo Hannu,
Möller Christer,
Gellerfors Pär,
Lannfelt Lars,
Bergström Joakim,
Ingelsson Martin
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12175
Subject(s) - alpha synuclein , lewy body , dementia with lewy bodies , genetically modified mouse , monoclonal antibody , pathology , parkinson's disease , antibody , dementia , epitope , amyloid (mycology) , chemistry , disease , biology , transgene , medicine , immunology , biochemistry , gene
Inclusions of intraneuronal alpha‐synuclein (α‐synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of α‐synuclein is a central feature of the disease pathogenesis. Among the different α‐synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mA b38F and mA b38E2, with high affinity and strong selectivity for large α‐synuclein oligomers were generated. These antibodies, which do not bind amyloid‐beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in α‐synuclein transgenic mice than linear epitope antibodies. An oligomer‐selective sandwich ELISA, based on mA b38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of α‐synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of α‐synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer‐selective α‐synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.