Hematopoietic CC-chemokine receptor 2 (CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease

Mol Med. 2012 Mar 30;18(1):297-313. doi: 10.2119/molmed.2011.00306.

Abstract

Monocytes emigrate from bone marrow, can infiltrate into brain, differentiate into microglia and clear amyloid β (Aβ) from the brain of mouse models of Alzheimer's disease (AD). Here we show that these mechanisms specifically require CC-chemokine receptor 2 (CCR2) expression in bone marrow cells (BMCs). Disease progression was exacerbated in APP(Swe)/PS1 mice (transgenic mice expressing a chimeric amyloid precursor protein [APPSwe] and human presenilin 1 [PS1]) harboring CCR2-deficient BMCs. Indeed, transplantation of CCR2-deficient BMCs enhanced the mnesic deficit and increased the amount of soluble Aβ and expression of transforming growth factor (TGF)-β1 and TGF-β receptors. By contrast, transplantation of wild-type bone marrow stem cells restored memory capacities and diminished soluble Aβ accumulation in APP(Swe)/PS1 and APP(Swe)/PS1/CCR2⁻/⁻ mice. Finally, gene therapy using a lentivirus-expressing CCR2 transgene in BMCs prevented cognitive decline in this mouse model of AD. Injection of CCR2 lentiviruses restored CCR2 expression and functions in monocytes. The presence of these cells in the brain of non-irradiated APP(Swe)/PS1/CCR2⁻/⁻ mice supports the concept that they can be used as gene vehicles for AD. Decreased CCR2 expression in bone marrow-derived microglia may therefore play a major role in the etiology of this neurodegenerative disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Avoidance Learning
  • Brain / metabolism
  • Brain / pathology
  • Cognition Disorders / metabolism*
  • Cognition Disorders / pathology
  • Cognition Disorders / physiopathology
  • Disease Models, Animal
  • Gene Expression
  • Hematopoietic Stem Cells / metabolism*
  • Male
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Plaque, Amyloid
  • Protein-Serine-Threonine Kinases / genetics
  • RNA, Messenger / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, CCR2 / metabolism*
  • Receptors, Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1 / genetics

Substances

  • Amyloid beta-Protein Precursor
  • Ccr2 protein, mouse
  • RNA, Messenger
  • Receptors, CCR2
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II