The Novel Use of Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) to Reverse Cerebral Amyloidosis and Cognitive Impairment in Alzheimer’s Disease Mouse Models: Insights from the Investigation of Rheumatoid Arthritis as a Negative Risk Factor for Alzheimer’s Disease
Degree Granting Department
Huntington Potter, Ph.D.
Inge Wefes, Ph.D.
Ray Widen, Ph.D.
Ronald Keller, Ph.D.
Andreas Seyfang, Ph.D.
Juan Sanchez-Ramos, Ph.D., M.D.
G-CSF, M-CSF, neuroinflammation, Aβ, Radial Arm Water Maze, Cognitive Interference task, transgenic mice, intrahippocampal, subcutaneous
For many years, it has been known that Rheumatoid arthritis (RA) is a negative risk factor for the development of Alzheimer’s disease (AD). It has been commonly assumed that RA patients’ usage of non-steroidal anti-inflammatory drugs (NSAIDs) have helped prevent the onset and progression of AD pathogenesis. Furthermore, experiments in animal models of Alzheimer’s disease have looked to inhibit inflammation, and have demonstrated some efficacy against AD-like pathology in these models. Thus many NSAID clinical trials have been performed over the years, but all have proven unsuccessful in AD patients. This suggests that intrinsic factors within RA pathogenesis itself may underlie RA’s protective effect.
My dissertation research goal was to investigate this inverse relationship between RA and AD, in order to more precisely pinpoint critical events in AD pathogenesis toward developing therapeutic strategies against AD. It seemed improbable that any secreted factors, produced in RA pathogenesis, could maintain high enough concentrations in the circulatory system to cross the blood brain barrier and inhibit AD pathogenesis, without affecting all other organ systems. It did seem possible that the leukocyte populations induced in RA, could traverse the circulatory system, extravasate into the brain parenchyma, and impede or reverse AD pathogenesis. We thus investigated the colony-stimulating factors, which are up-regulated in RA and which induce most of RA’s leukocytosis, on the pathology and behavior of transgenic AD mice. We found that G-CSF and more significantly, GM-CSF, reduced amyloidosis throughout the treated brain hemisphere one week following bolus intrahippocampal administration into AD mice. We then found that 20 days of subcutaneous injections of GM-CSF (the most amyloid-reducing CSF in the bolus experiment) significantly reduced brain amyloidosis and completely reversed cognitive impairment in aged cognitively-impaired AD mice, while increasing hippocampal synaptic area and microglial density. These findings, along with two decades of accrued safety data using Leukine, the recombinant human GM-CSF analogue, in elderly leukopenic patients, suggested that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD patients. It was also implied that age-related depressed hematopoiesis may contribute to AD pathogenesis.
Scholar Commons Citation
Boyd, Timothy David, "The Novel Use of Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) to Reverse Cerebral Amyloidosis and Cognitive Impairment in Alzheimer’s Disease Mouse Models: Insights from the Investigation of Rheumatoid Arthritis as a Negative Risk Factor for Alzheimer’s Disease" (2010). Graduate Theses and Dissertations.