Reparative Effects of Stem Cell Factor and Granulocyte Colony-Stimulating Factor in Aged APP/PS1 Mice.

Li-Ru Zhao,Xingzhi Guo,David Morgan,Yanying Liu

doi:10.14336/ad.2020.0201

Abstract

Alzheimer’s disease (AD), characterized by the accumulation of β-amyloid (Aβ) plaques and tau neurofibrillary tangles in the brain, neuroinflammation and neurodegeneration, is the most common form of neurodegenerative disease among the elderly. No effective treatment is available now in restricting the pathological progression of AD. The aim of this study is to determine the therapeutic efficacy of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in aged APPswe/PS1dE9 (APP/PS1) mice. SCF+G-CSF was subcutaneously injected for 12 days to 25-month-old male APP/PS1 mice. We observed that SCF+G-CSF treatment reduced the Aβ plaques in both the cortex and hippocampus. SCF+G-CSF treatment increased the association of TREM2+/Iba1+ cells with Aβ plaques and enhanced Aβ uptake by Iba1+ and CD68+cells in the brains of aged APP/PS1 mice. Importantly, cerebral expression area of P2RY12+and TMEM119+ homeostatic microglia and the branches of P2RY12+ homeostatic microglia were increased in the SCF+G-CSF-treated aged APP/PS1 mice. SCF+G-CSF treatment also decreased NOS-2 and increased IL-4 in the brains of aged APP/PS1 mice. Moreover, the loss of MAP2+dendrites and PSD-95+post-synapses and the accumulation of aggregated tau in the brains of aged APP/PS1 mice were ameliorated by SCF+G-CSF treatment. Furthermore, the density of P2RY12+ microglia was negatively correlated with Aβ deposits, but positively correlated with the densities of MAP2+ dendrites and PSD-95+ puncta in the brains of aged APP/PS1 mice. These findings reveal the therapeutic potential of SCF+G-CSF treatment in ameliorating AD pathology at the late stage.

Highlights

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, which leads to huge economic costs and social burden worldwide [1]
Using a widely-used mouse model of cerebral amyloidosis in AD research, the present study has demonstrated the therapeutic efficacy of combined Stem cell factor (SCF) and granulocyte colonystimulating factor (G-CSF) treatment in aged male amyloid precursor protein (APP)/PS1 mice
Our data have revealed that SCF+G-CSF treatment reduces diffuse and fibrillar Aβ deposits, increases the association of microglia/macrophages with senile plaques, and enhances Aβ uptake by microglia/macrophages in the brains of aged APP/PS1 mice

Summary

Introduction

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, which leads to huge economic costs and social burden worldwide [1]. A long-term study of monthly administration of a human monoclonal antibody, aducanumab, to mild AD patients for one year has shown reduced brain Aβ and slowed cognitive decline [12], leading to more recent AD clinical trials. In clinical studies, decreased levels of SCF and GCSF in the plasma have been observed in AD patients [30, 31]. It remains to be determined, whether exogenous administration of SCF and G-CSF could ameliorate pathological severity in AD. We have revealed that systemic administration of SCF+G-CSF in middle aged (9 months) APP/PS1 mice results in long-term (9 months) reductions in Aβ deposits [32]. Since AD predominantly affects elderly people, it is highly important to determine the efficacy of SCF+G-

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