Brain Advance Access published online on January 17, 2009
Brain, doi:10.1093/brain/awn331
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Powerful beneficial effects of macrophage colony-stimulating factor on β-amyloid deposition and cognitive impairment in Alzheimer's disease
1 Laboratory of Molecular Endocrinology, CHUL Research Center, CHUQ, 2705 Blvd Laurier, Quebec, QC, G1V 4G2 2 Department of Anatomy and Physiology, Faculty of Medicine, Université Laval, Quebec, QC, G1V 0A6, Canada 3 Biogen Idec, 14 Cambridge Center, Bio7, Cambridge, MA 02142, USA
Correspondence to:
Dr Serge Rivest, Laboratory of Molecular Endocrinology, 2705 Blvd Laurier, Local T-3-67, Quebec, G1V 4G2, Canada E-mail: serge.rivest{at}crchul.ulaval.ca
Alzheimer's disease is a major cause of dementia in humans. The appearance of cognitive decline is linked to the overproduction of a short peptide called β-amyloid (Aβ) in both soluble and aggregate forms. Here, we show that injecting macrophage colony-stimulating factor (M-CSF) to Swedish β-amyloid precursor protein (APPSwe)/PS1 transgenic mice, a well-documented model for Alzheimer's disease, on a weekly basis prior to the appearance of learning and memory deficits prevented cognitive loss. M-CSF also increased the number of microglia in the parenchyma and decreased the number of Aβ deposits. Senile plaques were smaller and less dense in the brain of M-CSF-treated mice compared to littermate controls treated with vehicle solution. Interestingly, a higher ratio of microglia internalized Aβ in the brain of M-CSF-treated animals and the phagocytosed peptides were located in the late endosomes and lysosomes. Less Aβ40 and Aβ42 monomers were also detected in the extracellular protein enriched fractions of M-CSF-treated transgenic mice when compared with vehicle controls. Finally, treating APPSwe/PS1 mice that were already demonstrating installed Aβ pathology stabilized the cognitive decline. Together these results provide compelling evidence that systemic M-CSF administration is a powerful treatment to stimulate bone marrow-derived microglia, degrade Aβ and prevent or improve the cognitive decline associated with Aβ burden in a mouse model of Alzheimer's disease.
Key Words: Alzheimer's disease; β-amyloid; microglia; M-CSF
Abbreviations: Aβ, β-amyloid; APP, β-amyloid precursor protein; APPswe, Swedish β-amyloid precursor protein; BMDM, bone marrow derived microglia; BSA, bovine serum albumin; CSFs, colony-stimulating factors; DPBS, Dulbecco's phosphate buffered saline; FBS, foetal bovine serum; GFP, green fluorescent protein; LAMP-2, lysosomal-associated membrane protein-2; MCI, mild cognitive impairment; M-CSF, macrophage colony-stimulating factor; M-CSFR, macrophage colony-stimulating factor receptor; PBS, phosphate buffered saline; PS1, presenilin-1; WT, wild-type
Received July 22, 2008. Revised November 6, 2008. Accepted November 10, 2008.