P3‐419: GM‐CSF up‐regulated in reumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice

Rheumatoid arthritis (RA) is a negative risk factor for the development of Alzheimer's disease (AD). While 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, up-regulated in RA, on the pathology and behavior of transgenic AD mice. 5μg bolus injections of macrophage, granulocyte, and granulocyte-macrophage colony- stimulating factors (MCSF, GCSF, 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 (aCSF)-injected contralateral sides as controls. 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. G-CSF and more significantly, GM-CSF reduced amyloidosis throughout the treated brain hemisphere one week following bolus administration to AD mice. Moreover, 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 GM-CSF, in elderly leukopenic patients, suggest that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD.