P4‐032: GM‐CSF REVERSES MEMORY DEFICITS IN NORMAL AGED MICE AND IN THE DP(16)1YEY MOUSE MODEL OF DOWN SYNDROME

Down syndrome (DS), the most common genetic cause of intellectual disability (ID), is characterized by mild-to-severe cognitive deficits and several neurological abnormalities, including impaired neurogenesis, decreased synaptogenesis, and reduced brain size, all of which are directly associated with ID. Everyone with DS develops Alzheimer's disease (AD) brain neuropathology by age 35, and most develop dementia. However, there are no pharmacotherapies for people with DS. Treatment of PS/APP AD mice with granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor, reversed cognitive deficits, reduced amyloidosis, and increased cerebral synaptophysin expression. GM-CSF is in Phase 2 clinical trials of AD subjects at the University of Colorado Rocky Mountain Alzheimer's Disease Center. To evaluate the potential efficacy of GM-CSF for ID in DS, we tested the performance of 3- and 12- to 14-month-old Dp16 male and female mice and their wild-type littermate controls in several behavioral assays before and after GM-CSF treatment. We also used immunohistochemical approaches to investigate potential brain neuropathology. Mice were injected subcutaneously with GM-CSF (5 μg/day; 5 days/week) or saline for 24 injections total over 29 days, and baseline assessments were started eight days before the first injection. On day 16, behavioral assessments were initiated as injections continued. On day 29, mice were perfused and brain tissues were fixed for immunohistochemistry. Prior to GM-CSF treatment, both male and female Dp16 mice showed elevated locomotor activity relative to wild-type controls in the open field assay. Male Dp16 mice were impaired in the RAWM, which was rescued by GM-CSF treatment (females were ineffective swimmers). GM-CSF treatment also enhanced learning and memory in wild-type controls in the RAWM. We observed abnormal morphology of GFAP-stained astrocytes in the hippocampi of Dp16 mice, which was rescued by GM-CSF treatment. Dp16 mice also showed a reduced number of calretinin-positive interneurons, which was increased following GM-CSF treatment. Our findings suggest that GM-CSF treatment rescues some behavioral deficits and brain neuropathology in Dp16 mice and enhances learning and memory in wild-type mice. The results of these studies will help determine whether GM-CSF/sargramostim/Leukine® may be considered as a potential therapeutic for people with DS.