Adverse effects of a SOD1-peptide immunotherapy on SOD1G93A mouse slow model of amyotrophic lateral sclerosis. (3rd December 2015)

• Record Type: Journal Article
• Authors: Sábado, J.; Casanovas, A.; Rodrigo, H.; Arqué, G.; Esquerda, J.E.
• Is Part Of: Neuroscience. Volume 310(2015)
• Page Start: 38
• Page End: 50
• Publication Date: 2015-12-03
• Subjects: ALS amyotrophic lateral sclerosis -- CS clinical score -- ELISA enzyme-linked immunosorbent assay -- FALS familial amyotrophic lateral sclerosis -- GFAP glial fibrillary acidic protein -- Iba-1 ionized calcium binding adaptor molecule -- IgG immunoglobulin G -- KLH keyhole limpet hemocyanin -- MN motoneuron -- OFT open-field test -- PB phosphate buffer -- PBS phosphate-buffered saline -- PFA paraformaldehyde -- SEDI SOD1-exposed dimmer interface -- SOD1 superoxide dismutase 1 -- WT wild type -- α-syn α-synuclein; amyotrophic lateral sclerosis -- immunotherapy -- superoxide dismutase -- conformational-specific antibody -- microglia -- neuroinflammation; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.09.027
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: An immunotherapeutic assay in SOD1G93A slow ALS mice model was performed. As antigen for vaccination, a SOD1 peptide was used. Immunotherapy does not result in an improved clinical or pathological outcome. Vaccinated animals showed increased neuroinflammation in the spinal cord. Vaccine induced an adverse response that counteracts its possible beneficial effect. Abstract: Previous reports from our lab had shown that some anti-purinergic receptor P2X4 antibodies cross-reacted with misfolded forms of mutant Cu/Zn superoxide dismutase 1 (SOD1), linked to amyotrophic lateral sclerosis (ALS). Cross-reactivity could be caused by the abnormal exposure of an epitope located in the inner hydrophobic region of SOD1 that shared structural homology with the P2X4-immunizing peptide. We had previously raised antibodies against human SOD1 epitope mimicked by the P2X4 immunizing peptide. One of these antibodies, called AJ10, was able to recognize mutant/misfolded forms of ALS-linked mutant SOD1. Here, we used the AJ10 antigen as a vaccine to target neurotoxic species of mutant SOD1 in a slow mouse model of ALS. However, the obtained results showed no improvement in life span, disease onset or weight loss in treated animals; we observed an increased microglial neuroinflammatory response and high amounts of misfolded SOD1 accumulated within spinal cord neurons after AJ10 immunization. An increase of immunoglobulin G deposits was also found due to the treatment. Finally, a significantly worse clinical evolution was displayed by an impairment on motor function as a consequence of AJ10 peptide immunization.