Journal of Neuroimmune Pharmacology

, Volume 7, Issue 1, pp 202–214

Chronological Age Impacts Immunotherapy and Monocyte Uptake Independent of Amyloid Load

  • Qingyou Li
  • Lori Lebson
  • Daniel C. Lee
  • Kevin Nash
  • Jan Grimm
  • Arnon Rosenthal
  • Maj-Linda B. Selenica
  • Dave Morgan
  • Marcia N. Gordon
ORIGINAL ARTICLE

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 

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Qingyou Li
    • 1
    • 2
  • Lori Lebson
    • 1
    • 5
  • Daniel C. Lee
    • 1
    • 3
  • Kevin Nash
    • 1
    • 2
  • Jan Grimm
    • 4
    • 6
  • Arnon Rosenthal
    • 4
    • 7
  • Maj-Linda B. Selenica
    • 1
    • 2
  • Dave Morgan
    • 1
    • 2
  • Marcia N. Gordon
    • 1
    • 2
  1. 1.USF Health Byrd Alzheimer’s InstituteTampaUSA
  2. 2.Department of Molecular Pharmacology and PhysiologyUniversity of South FloridaTampaUSA
  3. 3.College of PharmacyUniversity of South FloridaTampaUSA
  4. 4.Rinat NeuroscienceSouth San FranciscoUSA
  5. 5.Department of NeurologyJohns Hopkins UniversityBaltimoreUSA
  6. 6.Neurimmune TherapeuticsSchlierenSwitzerland
  7. 7.MazorX Inc.Redwood CityUSA

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