Research Article: Stem cell factor and granulocyte colony-stimulating factor reduce β-amyloid deposits in the brains of APP/PS1 transgenic mice

Date Published: March 15, 2011

Publisher: BioMed Central

Author(s): Bin Li, Maria E Gonzalez-Toledo, Chun-Shu Piao, Allen Gu, Roger E Kelley, Li-Ru Zhao.


Alzheimer’s disease (AD) is widely recognized as a serious public health problem and heavy financial burden. Currently, there is no treatment that can delay or stop the progressive brain damage in AD. Recently, we demonstrated that stem cell factor (SCF) in combination with granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) has therapeutic effects on chronic stroke. The purpose of the present study is to determine whether SCF+G-CSF can reduce the burden of β-amyloid deposits in a mouse model of AD.

APP/PS1 transgenic mice were used as the model of AD. To track bone marrow-derived cells in the brain, the bone marrow of the APP/PS1 mice was replaced with the bone marrow from mice expressing green fluorescent protein (GFP). Six weeks after bone marrow transplantation, mice were randomly divided into a saline control group and a SCF+G-CSF-treated group. SCF in combination with G-CSF was administered subcutaneously for 12 days. Circulating bone marrow stem cells (CD117+ cells) were quantified 1 day after the final injection. Nine months after treatment, at the age of 18 months, mice were sacrificed. Brain sections were processed for immunohistochemistry to identify β-amyloid deposits and GFP expressing bone marrow-derived microglia in the brain.

Systemic administration of SCF+G-CSF to APP/PS1 transgenic mice leads to long-term reduction of β-amyloid deposition in the brain. In addition, we have also observed that the SCF+G-CSF treatment increases circulating bone marrow stem cells and augments bone marrow-derived microglial cells in the brains of APP/PS1 mice. Moreover, SCF+G-CSF treatment results in enhancement of the co-localization of bone marrow-derived microglia and β-amyloid deposits in the brain.

These data suggest that bone marrow-derived microglia play a role in SCF+G-CSF-induced long-term effects to reduce β-amyloid deposits. This study provides insights into the contribution of the hematopoeitic growth factors, SCF and G-CSF, to limit β-amyloid accumulation in AD and may offer a new therapeutic approach for AD.

Partial Text

Alzheimer’s disease (AD) is the major cause of dementia and the sixth leading cause of death in the United States [1]. Currently, no treatment has been proven to stop AD. Although the cause of AD remains uncertain, substantial evidence shows that toxic β-amyloid peptide plays a critical role in the progress of this devastating disease [2].

All procedures were approved by the Institutional Animal Care and Use Committee of Louisiana State University Health Sciences Center and are in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

The main findings of the present study are that systemic administration of SCF+G-CSF in APP/PS1 transgenic mice leads to long-lasting effects to reduce the β-amyloid burden. In addition, we have also revealed that the treatment enhances the co-localization of bone marrow-derived microglia and β-amyloid deposits in the brains of APP/PS1 mice.

In summary, the present study provides evidence that SCF+G-CSF treatment results in a long-term decrease in β-amyloid load in APP/PS1 transgenic mice. This therapeutic affect may be associated with SCF+G-CSF-induced increase in clearance of β-amyloid deposits through the enhancement of bone marrow-derived microglial cells. These data suggest that treatment with the hematopoeitic growth factors SCF and G-CSF may open an new avenue to develop therapeutic strategies for improving the health of individuals who suffer from AD.

AD: Alzheimer’s disease; APP: amyloid precursor protein; G-CSF: granulocyte colony-stimulating factor; GFP: green fluorescent protein; PBS: phosphate-buffered saline; PS1: presenilin 1; SCF: stem cell factor.

The authors declare that they have no competing interests.

BL acquired and analyzed immunohistochemistry data and prepared the draft of the manuscript. MEG-T performed bone marrow transplantation and drug administration. MEG-T and AG contributed to maintenance and genotyping of transgenic mice. C-SP performed collection of bone marrow cells and flow cytometry. REK provided suggestions for the manuscript. L-RZ contributed to experimental design, supervision of data collection and analysis, and revision of the final version of manuscript.




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