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PrP antibodies do not trigger mouse hippocampal neuron apoptosis
Peter-Christian Klöhn1, Michael Farmer, Jacqueline M Linehan
1Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Abstract:
Intraperitoneal administration of ICSM18 and 35, monoclonal antibodies against prion protein (PrP), has been shown to significantly delay the onset of prion disease in mice, and humanized versions are candidate therapeutics for prion and Alzheimer's diseases. However, a previous report of severe and widespread apoptosis after intracerebral injection of anti-PrP monoclonal antibodies raised concerns about such therapy and led to an influential model of prion neurotoxicity via cross-linking of cell surface PrP by disease-related PrP aggregates. In extensive studies including ICSM18 and 35, fully humanized ICSM18, and the previously reported proapoptotic antibodies, we found no evidence of apoptosis, thereby questioning this model of prion neurotoxicity.
Insights
Monoclonal antibodies targeting prion protein (PrP) show therapeutic potential for prion and Alzheimer's diseases. Extensive studies found no evidence of apoptosis, challenging a key model of prion neurotoxicity.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Monoclonal antibodies (mAbs) against prion protein (PrP) like ICSM18 and 35 delay prion disease in mice.
- Humanized versions are investigated as therapeutics for prion and Alzheimer's diseases.
- Previous studies reported apoptosis following intracerebral anti-PrP mAb injection, proposing a neurotoxicity model.
Purpose of the Study:
- To investigate the potential for apoptosis induced by anti-PrP mAbs.
- To evaluate the validity of the prion neurotoxicity model based on PrP cross-linking.
Main Methods:
- Administration of anti-PrP mAbs (ICSM18, 35, humanized ICSM18) and previously reported proapoptotic antibodies.
- Extensive studies to assess for evidence of apoptosis.
Main Results:
- No evidence of apoptosis was observed in response to anti-PrP mAb administration.
- The findings question the proposed mechanism of prion neurotoxicity via PrP cross-linking.
Conclusions:
- Anti-PrP monoclonal antibodies do not induce apoptosis.
- The influential model of prion neurotoxicity via cross-linking of cell surface PrP is challenged by these findings.
