title: GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice.
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 microg 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 5 microg 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.
authors.affiliation: USF Health Byrd Alzheimer's Center and Research Institute, Tampa, FL 33613, USA.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Boyd
authors.forename: Steven P
authors.initials: SP
authors.lastname: Bennett
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Nicholas
authors.initials: N
authors.lastname: Governatori
authors.forename: Melissa
authors.initials: M
authors.lastname: Runfeldt
authors.forename: Michelle
authors.initials: M
authors.lastname: Norden
authors.forename: Jaya
authors.initials: J
authors.lastname: Padmanabhan
authors.forename: Peter
authors.initials: P
authors.lastname: Neame
authors.forename: Inge
authors.initials: I
authors.lastname: Wefes
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez-Ramos
authors.forename: Gary W
authors.initials: GW
authors.lastname: Arendash
authors.forename: Huntington
authors.initials: H
authors.lastname: Potter
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D000686:Amyloidosis / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012307:Risk Factors; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor