GM-CSF Upregulated in Rheumatoid Arthritis Reverses Cognitive Impairment and Amyloidosis in Alzheimer Mice

Article type: Research Article

Authors: Boyd, Tim D.^{a; b; c;} | Bennett, Steven P.^{a; b; c;} | Mori, Takashi^d | Governatori, Nicholas^e | Runfeldt, Melissa^e | Norden, Michelle^a | Padmanabhan, Jaya^{a; b} | Neame, Peter^{a; b} | Wefes, Inge^{b; c} | Sanchez-Ramos, Juan^{a; f} | Arendash, Gary W.^{e; g} | Potter, Huntington^{a; b; c; g; *}

Affiliations: [a] USF Health Byrd Alzheimer's Center and Research Institute, Tampa, FL, USA | [b] Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA | [c] Eric Pfeiffer Suncoast Gerontology Center, University of South Florida, Tampa, FL, USA | [d] Departments of Biomedical Sciences and Pathology, Saitama Medical Center and Saitama Medical University, Kamoda, Kawagoe, Saitama, Japan | [e] Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA | [f] epartment of Neurology, College of Medicine, University of South Florida, Tampa, FL, USA | [g] Florida Alzheimer's Disease Research Center, University of South Florida, Tampa, FL, USA

Correspondence: [*] Correspondence to: Huntington Potter, PhD, USF Health Byrd, Sr. Alzheimer's Center and Research Institute, 4001 E. Fletcher Avenue, Tampa, FL 33613, USA. Tel.: +1 813 396 0660; Fax: +1 813 971 0373; E-mail: [email protected].

Note: [1] Both authors contributed equally to this work.

Note: [] Handling Associate Editor: Luciano D’Adamio

Abstract: Rheumatoid arthritis (RA) is a negative risk factor for the development of Alzheimer's disease (AD). While it has been commonly assumed that RA patients' usage of non-steroidal anti-inflammatory drugs (NSAIDs) helped prevent onset and progression of AD, NSAID clinical trials have proven unsuccessful in AD patients. To determine whether intrinsic factors within RA pathogenesis itself may underlie RA's protective effect, we investigated the activity of colony-stimulating factors, upregulated in RA, on the pathology and behavior of transgenic AD mice. 5 μg bolus injections of macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factors (M-CSF, G-CSF, or GM-CSF) were administered unilaterally into the hippocampus of aged cognitively-impaired AD mice and the resulting amyloid load reductions determined one week later, using the artificial cerebrospinal fluid-injected contralateral sides as controls. G-CSF and more significantly, GM-CSF reduced amyloidosis throughout the treated brain hemisphere one week following bolus administration to AD mice. 20 daily subcutaneous injections of 5μg of GM-CSF (the most amyloid-reducing CSF in the bolus experiment) were administered to balanced cohorts of AD mice after assessment in a battery of cognitive tests. Reductions in amyloid load and improvements in cognitive function were assessed. Subcutaneous GM-CSF administration significantly reduced brain amyloidosis and completely reversed the cognitive impairment, while increasing hippocampal synaptic area and microglial density. These findings, along with two decades of accrued safety data using Leukine, recombinant human GMCSF, in elderly leukopenic patients, suggest that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD.

Keywords: Alzheimer's disease, amyloid-β, cognitive interference task, granulocyte-macrophage colony-stimulating factor, intrahippocampal, radial arm water maze, rheumatoid arthritis, subcutaneous, transgenic mice

DOI: 10.3233/JAD-2010-091471

Journal: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 507-518, 2010