Abstract
One vexing issue in biomedical research is the failure of many therapies to translate from success in animal models to effective treatment of human disease. One significant difference between the animal models and the human disease is the age of the subject. Cancer, stroke and Alzheimer’s occur mainly in humans beyond the 75% mean survival age, while most mouse models use juvenile or young adult animals. Here we compare two mouse models of amyloid deposition, the Tg2576 APP model and the more aggressive APP+PS1 model in which a mutant presenilin1 gene is overexpressed with Tg2576. Middle-aged APP+PS1 mice and aged APP mice have similar degrees of amyloid pathology with a few differences that may partially explain some of the differences between the two age cohorts. The first study evaluated production of microhemorrhage by a monoclonal anti-Aβ antibody. We found that in spite of greater amyloid clearance in middle-aged APP+PS1 mice than aged APP mice, the microhemorrhage only developed in old animals. This argues that preclinical studies of immunotherapy in young or middle-aged mice may not predict this potential liability in clinical trials. A second study evaluated the infiltration of systemically injected GFP labeled monocytes into the CNS. Here we find that infiltration is greater in aged mice than middle-aged mice, in spite of greater total Aß staining in the middle–aged animals. We conclude that preclinical studies should be conducted in aged animal models as well as young mice to better prepare for unintended consequences in the human trial.
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Conflicts of Interest
DM has consulted with the following pharmaceutical companies; Eisai, Forest, Merck, Pfizer (and Wyeth), Lundbeck, Baxter, Bristol-Myers-Squibb, NeurImmune, Bioarctic, Elan. JG and AR were employees of Rinat Neuroscience (now Rinat-Pfizer) when this work was performed.
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Drs. Li and Lebson contributed equally to this work as co-first authors.
Guarantors. D Morgan and MN Gordon
Support. This work was supported by AG 04418 and AG 18478 (to DM), and AG 15490 (to MNG). Antibody 2H6 was donated by Rinat Neuroscience under terms of an MTA, but all research funds to support this work were from NIH.
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Li, Q., Lebson, L., Lee, D.C. et al. Chronological Age Impacts Immunotherapy and Monocyte Uptake Independent of Amyloid Load. J Neuroimmune Pharmacol 7, 202–214 (2012). https://doi.org/10.1007/s11481-011-9329-9
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DOI: https://doi.org/10.1007/s11481-011-9329-9