THE THERAPEUTIC EFFECTS OF HEMATOPOIETIC GROWTH FACTORS IN A MOUSE MODEL OF CEREBRAL AMYLOIDOSIS

Abstract

Emerging evidence has revealed that dysfunction of the innate immune system for Aβ clearance plays a key role in cerebral Aβ deposition and in Alzheimer's disease progression. Our earlier study has demonstrated that the combination of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF), the two essential hematopoietic growth factors, increases bone marrow-derived monocyte/macrophage (BMDM) recruitment, enhances the association of BMDMs with amyloid plagues, and reduces Aβ deposits in APP/PS1 mice 9 months after treatment. The aim of this study is to further identify the therapeutic efficacy of SCF, G-CSF, or SCF+G-CSF in APP/PS1 mice. Male APP/PS1 mice (10 month old) were randomized to receive 12- day injections (s.c.) of either vehicle solution, SCF (200μg/kg), G-CSF (50μg/kg), or SCF+G-CSF. Age-matched wild-type (WT) mice served as normal controls. The spatial learning and memory was evaluated by water maze testing at 3 and 7 months post-treatment. The Aβ load in the brain was determined by ELISA, immunohistochemistry (IHC) and Thioflavin-S staining 8 months after treatment. APP/PS1 control mice spent significantly longer time to find the hidden platform than WT mice. SCF+G-CSF-treated APP/PS1mice found the platform significantly faster than vehicle controls, SCF alone- or G-CSF alone-treated APP/PS1 mice 3 months after treatment. At this time point, no difference was found between SCF+G-CSF-treated APP/PS1mice and WT mice, but significant difference was observed between SCF- or G-CSF-treated APP/PS1mice and WT mice. At 7 months post-treatment, the latency to find the platform was significantly reduced in SCF+G-CSF-treated or SCF-treated APP/PS1 mice. Eight months after treatment, only SCF+G-CSF treatment showed a significant reduction of Aβ1–40, Aβ 1–42. The deposition of Aβ (4G8+, Thioflavin-S+) was significantly decreased by SCF+G-CSF in both the cortex and hippocampus, while G-CSF alone only showed reduction in the hippocampus of APP/PS1 mice. SCF+G-CSF has synergistic effects in long-term improvement of cognitive function, and long-lasting reduction of brain Aβ load in APP/PS1mice. This study suggests a robust therapeutic potential of SCF and G-CSF combination over SCF or G-CSF alone in treatment of Alzheimer's disease. This study was supported by the NIA/NIH in the United States (R01AG051674).