ORIGINAL ARTICLE

Journal of Neuroimmune Pharmacology

, Volume 7, Issue 1, pp 202-214

Chronological Age Impacts Immunotherapy and Monocyte Uptake Independent of Amyloid Load

  • Qingyou LiAffiliated withUSF Health Byrd Alzheimer’s InstituteDepartment of Molecular Pharmacology and Physiology, University of South Florida
  • , Lori LebsonAffiliated withUSF Health Byrd Alzheimer’s InstituteDepartment of Neurology, Johns Hopkins University
  • , Daniel C. LeeAffiliated withUSF Health Byrd Alzheimer’s InstituteCollege of Pharmacy, University of South Florida
  • , Kevin NashAffiliated withUSF Health Byrd Alzheimer’s InstituteDepartment of Molecular Pharmacology and Physiology, University of South Florida
  • , Jan GrimmAffiliated withRinat NeuroscienceNeurimmune Therapeutics
  • , Arnon RosenthalAffiliated withRinat NeuroscienceMazorX Inc.
  • , Maj-Linda B. SelenicaAffiliated withUSF Health Byrd Alzheimer’s InstituteDepartment of Molecular Pharmacology and Physiology, University of South Florida
  • , Dave MorganAffiliated withUSF Health Byrd Alzheimer’s InstituteDepartment of Molecular Pharmacology and Physiology, University of South Florida Email author 
  • , Marcia N. GordonAffiliated withUSF Health Byrd Alzheimer’s InstituteDepartment of Molecular Pharmacology and Physiology, University of South Florida

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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.

Keywords

Amyloid Immunotherapy Microhemorrhage Monocyte Infiltration Transgenic mice