Combined Effects of Hematopoietic Progenitor Cell Mobilization from Bone Marrow by Granulocyte Colony Stimulating Factor and AMD3100 and Chemotaxis into the Brain Using Stromal Cell‐Derived Factor‐1α in an Alzheimer's Disease Mouse Model

Abstract

Transplantation of bone marrow-derived stem cells (BMSCs) has been suggested as a potential therapeutic approach to prevent neurodegenerative diseases, but it remains problematic due to issues of engraftment, potential toxicities, and other factors. An alternative strategy is pharmacological-induced recruitment of endogenous BMSCs into an injured site by systemic administration of growth factors or chemokines. Therefore, the aim of this study was to examine the effects of therapy involving granulocyte colony stimulating factor (G-CSF)/AMD3100 (CXCR4 antagonist) and stromal cell-derived factor-1α (SDF-1α) on endogenous BM-derived hematopoietic progenitor cell (BM-HPC) recruitment into the brain of an Alzheimer's disease (AD) mouse model. To mobilize BM-HPCs, G-CSF was injected intraperitoneally and boosted by AMD3100. Simultaneously, these mice received an intracerebral injection with SDF-1α to induce migration of mobilized BM-HPCs into brain. We found that the memory deficit in the AD mice was significantly improved by these treatments, but amyloid β deposition was unchanged. Interestingly, microglial activation was increased with alternative activation of microglia to a neuroprotective phenotype. Furthermore, by generating an amyloid precursor protein/presenilin 1-green fluorescent protein (GFP) chimeric mouse, we ascertained that the GFP positive microglia identified in the brain were BM-derived. Additionally, increased hippocampal neurogenesis and improved memory was observed in mice receiving combined G-CSF/AMD3100 and SDF-1α, but not in controls or animals receiving each treatment alone. These results suggest that SDF-1α is an effective adjuvant in inducing migration into brain of the endogenous BM-HPCs, mobilized by G-CSF/AMD3100, and that the two can act synergistically to produce a therapeutic effect. This approach warrants further investigation as a potential therapeutic option for the treatment of AD patients in the future.