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
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 APPSwe/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 APPSwe/PS1 and APPSwe/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 nonirradiated APPSwe/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.
The Canadian Institutes in Health Research and Neuroscience Canada (Brain Repair Program) supported this research. G Naert was supported by a postdoctoral fellowship from the Alzheimer Society of Canada. S Rivest is a Canadian Research Chair in Neuroimmunology. We acknowledge the contribution of Mohammed Filali, Martine Lessard, Paul Préfontaine, Denis Soulet and Marie-Michèle Plante for technical help. We are grateful to Matthias Mack (Universitätsklinikum Regensburg Innere Medizin II/Nephrologie-Transplantation, Regensburg, Germany) for the gift of the anti-CCR2 antibody (Ab MC-21).
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