Modifications of hippocampal circuits and early disruption of adult neurogenesis in the tg2576 mouse model of Alzheimer's disease

PLoS One. 2013 Sep 27;8(9):e76497. doi: 10.1371/journal.pone.0076497. eCollection 2013.

Abstract

At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer's pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / physiopathology
  • Animals
  • Biomarkers / metabolism
  • Calbindin 1 / metabolism
  • Cell Count
  • Cell Movement
  • Dentate Gyrus / metabolism
  • Dentate Gyrus / pathology
  • Dentate Gyrus / physiopathology
  • Disease Models, Animal
  • Disease Progression
  • Gene Expression Regulation
  • Hippocampus / pathology*
  • Hippocampus / physiopathology*
  • Male
  • Mice
  • Mice, Transgenic
  • Neurogenesis*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuropeptide Y / metabolism
  • Time Factors

Substances

  • Biomarkers
  • Calbindin 1
  • Neuropeptide Y

Grant support

C. Rampon acknowledges the support of the Agence Nationale pour la Recherche (ANR-06-JCJC and ANR-10-05-MALZ); the Centre National de la Recherche Scientifique (CNRS), the University of Toulouse, and the Region Midi-Pyrénées; L. Verret was supported by ANR-06-JCJC, the France Alzheimer Association, the Singer-Polignac Foundation, and the Philippe Foundation Awards. A. Krezymon and K. Richetin were supported by the French Ministry of Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.