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Acta Neuropathologica

, Volume 120, Issue 5, pp 605–621 | Cite as

Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice

  • Julie Blanchard
  • Lukas Wanka
  • Yunn-Chyn Tung
  • María del Carmen Cárdenas-Aguayo
  • Frank M. LaFerla
  • Khalid Iqbal
  • Inge Grundke-IqbalEmail author
Original Paper

Abstract

In addition to the occurrence of numerous neurofibrillary tangles and Aβ plaques, neurogenesis and neuronal plasticity are markedly altered in Alzheimer disease (AD). Although the most popular therapeutic approach has been to inhibit neurodegeneration, another is to promote neurogenesis and neuronal plasticity by utilizing the regenerative capacity of the brain. Here we show that, in a transgenic mouse model of AD, 3xTg-AD mice, there was a marked deficit in neurogenesis and neuroplasticity, which occured before the formation of any neurofibrillary tangles or Aβ plaques and was associated with cognitive impairment. Furthermore, peripheral administration of Peptide 6, an 11-mer, which makes an active region of ciliary neurotrophic factor (CNTF, amino acid residues 146–156), restored cognition by enhancing neurogenesis and neuronal plasticity in these mice. Although this treatment had no detectable effect on Aβ and tau pathologies in 9-month animals, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and cerebral cortex. These findings, for the first time, demonstrate the possibility of therapeutic treatment of AD and related disorders by peripheral administration of a peptide corresponding to a biologically active region of CNTF.

Keywords

Alzheimer disease CNTF Cognition Neurogenesis Neuronal plasticity Tau hyperphosphorylation 

Notes

Acknowledgments

We thank Prof. Dr. Peter R. Schreiner and Dr. Heike Hausmann, Institute of Organic Chemistry, University of Giessen (Germany) for the NMR characterization. ESI–MS analysis for Peptide 6 by Dr. David Bolton is gratefully acknowledged. We are grateful to Dr. George Merz for confocal assistance and to Mrs. Janet Murphy for secretarial assistance. This work was supported in part by the New York State Office of People With Developmental Disabilities; EVER NeuroPharma GmbH, Unterach, Austria; and the T.L.L. Temple Foundation Discovery Award for Alzheimer Disease Research, the Alzheimer Association, Chicago, IL.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Julie Blanchard
    • 1
  • Lukas Wanka
    • 1
    • 3
  • Yunn-Chyn Tung
    • 1
  • María del Carmen Cárdenas-Aguayo
    • 1
  • Frank M. LaFerla
    • 2
  • Khalid Iqbal
    • 1
  • Inge Grundke-Iqbal
    • 1
    Email author
  1. 1.Department of NeurochemistryNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandUSA
  2. 2.Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurobiological DisordersUniversity of CaliforniaIrvineUSA
  3. 3.Institute for Organic ChemistryJustus-Liebig-UniversityGiessenGermany

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