Disease-Modifying Effects of Filgastrim in a Mouse Model of AD

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Abstract/Summary Filgastrim (granulocyte colony stimulating factor or G-CSF) is a multi-modal hematopoietic growth factor used routinely in the hematology/oncology setting but reports of its benefits for brain diseases are appearing in the literature. Preliminary studies in a mouse model of Alzheimer's disease (AD) in our laboratory suggests it has both pro-cognitive and disease-modifying effects. The mechanisms responsible for these profound effects are not clear and development of G-CSF as a therapeutic agent for patients with AD warrants pre-clinical research. Objectives: The proposed studies are designed to elucidate the cellular and molecular mechanisms by which G-CSF reduces amyloid deposition/levels, stimulates hippocampal neurogenesis and restores synaptic functional activity in a mouse model of AD. Aim 1: The hypothesis that enhanced trafficking of bone-marrow derived cells from blood to brain and/or increased microglial and phagocytic activity is responsible for the decrease in beta-amyloid (A-¿) deposition will be tested in a chimeric tg AD mouse in which bone marrow derived cells express green fluorescent protein (GFP). Aim 2: To test the hypothesis that the pro-cognitive effects of G-CSF are mediated by direct actions on neural progenitor cells and neurons, the extent to which G-CSF promotes neurogenesis and/or promotes recovery of hippocamapal synaptic function and structure will be tested with neuroanatomical and electrophysiological techniques. Aim 3: At an intracellular level, mechanistic studies will elucidate a novel signaling pathway triggered by G-CSF that involves switching to an alternatively spliced variant of protein kinase C (PKC-delta2) that stimulates hippocampal neurogenesis and inhibits poly- phosphorylation of Tau, both which are postulated to underlie improved hippocampal synaptic function. Methods: Cellular and molecular biology techniques, immunohistochemistry, hippocampal slice electrophysiology and behavioral analysis will be employed. Chimeric tg AD mice engrafted with green fluorescent protein expressing (GFP+) bone marrow cells will be generated to determine the extent to which peripherally derived microglia and other bone marrow-derived cells contribute to amyloid reduction and/or neurogenesis. Findings to date: Administration of G-CSF to cognitively-impaired tg AD mice (APP+PS1) reversed the impaired cognitive performance and significantly decreased A¿ deposition in hippocampus and entorhinal cortex. G-CSF-treated tg AD mice also revealed a significant increase in total microgliosis and increased areas of synaptophysin immunostaining in hippocamal CA1 and CA3 regions. Additional preliminary results obtained from G-CSF administration to tg AD mice include stimulation of hippocampal neurogenesis and improvement of electrophysiological function in hippocampal slices. Clinical relevance: G-CSF is routinely and safely used to treat neutropenia and to stimulate hematopoietic stem cell generation in healthy bone marrow donors. The cognitive-enhancing and potential disease-modifying effects of G-CSF in a mouse model of AD provides a strong impetus for clinical trials to reverse or forestall progression of dementia in AD patients. Relevance to VA Mission: AD is an incurable, age-dependent dementing disease with a prevalence of 5 million in the US. As the veteran population ages, the prevalence of AD will increase, resulting in overwhelming demands on the VA health care system. From both humanitarian and socio-economic perspectives, there is an urgent need for disease-modifying medications that delay or reverse the progressive dementia of AD.