Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer's disease.
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 beta-amyloid (Abeta) in both soluble and aggregate forms. Here, we show that injecting macrophage colony-stimulating factor (M-CSF) to Swedish beta-amyloid precursor protein (APP(Swe))/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 Abeta 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 Abeta in the brain of M-CSF-treated animals and the phagocytosed peptides were located in the late endosomes and lysosomes. Less Abeta(40) and Abeta(42) monomers were also detected in the extracellular protein enriched fractions of M-CSF-treated transgenic mice when compared with vehicle controls. Finally, treating APP(Swe)/PS1 mice that were already demonstrating installed Abeta 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 Abeta and prevent or improve the cognitive decline associated with Abeta burden in a mouse model of Alzheimer's disease.
Boissonneault
Vincent
V
Laboratory of Molecular Endocrinology, CHUL Research Center, CHUQ, 2705 Blvd Laurier, Quebec, G1V 4G2, Canada.
Filali
Mohammed
M
Lessard
Martine
M
Relton
Jane
J
Wong
Gordon
G
Rivest
Serge
S
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D011992:Endosomes / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology
D016229:Amyloid beta-Peptides; D016173:Macrophage Colony-Stimulating Factor