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

Abstract

IntroductionAlzheimer'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.MethodsAPP/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.ResultsSystemic 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.ConclusionsThese 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.

Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL

“…Bone marrow-derived microglia are not increased by SCF + G-CSF in the conditions of CADASIL (present study) and chronic stroke (Piao et al, 2009), but SCF + G-CSF increases the bone marrow-derived microglia in the brains of mice carrying Alzheimer's disease genes (Li et al, 2011). In the chronic stroke brain, bone marrow-derived endothelia are increased by SCF + G-CSF treatment, while this type of cell appears to be decreased by SCF + G-CSF in CADASIL brain (present study).…”

Key inflammatory pathway activations in the MCI stage of Alzheimer’s disease

“…It has been noted to mediate chemoattractant activity for neural stem/progenitor cell migration and thought to play a repair role in models of stroke . In the context of AD it has been reported to be low in the CSF and plasma of AD patients and therapeutic effects of systemic SCF administration in mice models have shown promise in reducing amyloid …”

The computational power of astrocyte mediated synaptic plasticity

“…Thanks to those receptors astrocytes are not only capable to respond to the classical neurotransmitters glutamate and γ-aminobutyric acid (GABA) released from synapses [through metabotropic glutamate receptors (mGluRs) mGluR1-5 and GABA B receptors respectively; Pasti et al, 1997; Kang et al, 1998] but also to neuromodulators like acetylcholine (Takata et al, 2011; Navarrete et al, 2012) and dopamine (Khan et al, 2001). Moreover, purines like adenosine-5′-triphosphate (ATP) and adenosine (co-)released from synapses or other astrocytes can be sensed by astrocytes (Jourdain et al, 2007; Santello et al, 2011) and play a role in the propagation/amplification of Ca 2+ signals through the astrocytic syncytium (Poskanzer and Yuste, 2011) or serve as a signal for microglial reaction (Haynes et al, 2006). In addition to sensing axonal release of transmitters, astrocytes have been shown to respond to so-called retrograde signals: transmitters of postsynaptic or dendritic origin (Bernardinelli et al, 2011).…”

“…Interfering with astrocyte signaling reduces the power of slow oscillations in vivo (Fellin et al, 2009), presumably through modulation of NMDARs and adenosine A1 receptors. Furthermore, in vitro experiments have shown that astrocytes control the frequency of cortical up-states (Poskanzer and Yuste, 2011). …”