Powerful beneficial effects of macrophage colony-stimulating factor on  -amyloid deposition and cognitive impairment in Alzheimer's disease

Abstract

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.

Interleukin-34 Selectively Enhances the Neuroprotective Effects of Microglia to Attenuate Oligomeric Amyloid-β Neurotoxicity

“…Senile plaques were smaller, and microglia phagocytosed A␤ in the brain of mice treated with M-CSF. 34 These data indicate that the mechanism of neuroprotection by IL-34 is different from that of M-CSF. Recent reports have demonstrated that IL-34 and M-CSF differ in their structure and the CSF1R domains that they bind, which causes different bioactivities and signal activation kinetics.…”

Intracerebral Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Reduces Amyloid-Beta Deposition and Rescues Memory Deficits in Alzheimer's Disease Mice by Modulation of Immune Responses

“…Lee, Jin, Endo et al Some reports have previously shown that microglia are unable to eliminate Ab plaques, release cytotoxic cytokines, and participate in plaque formation as AD progresses [36,37]. However, Boissonneault et al [38] recently reported that M-CSF increases microglial cell number and stimulates Ab degradation. In addition, Ohtaki et al [17] suggested that BM-MSC treatment increases immune responses, including microglia activation and secretion of neuroprotective cytokines in ischemia mouse models.…”

TREM2 enables amyloid β clearance by microglia

“…In this regard, injecting macrophage colony-stimulating factor (M-CSF) to transgenic mice that spontaneously develop AD on a weekly basis prior to the appearance of learning and memory deficits prevented cognitive loss [4]. The treatment also restored the number of Ly6Chigh (e.g., M1) monocytes in the blood and greatly decreased Aβ levels [5].…”