Neuron loss in the brain starts in childhood, increases exponentially with age and is halted by GM-CSF treatment in Alzheimer’s disease

Abstract

SummaryAging increases the risk of neurodegeneration, cognitive decline, and Alzheimer’s disease (AD). Currently no means exist to measure neuronal cell death during life or to prevent it. Here we show that cross-sectional measures of human plasma proteins released from dying/damaged neurons (ubiquitin C-terminal hydrolase-L1/UCH-L1 and neurofilament light/NfL) become exponentially higher from age 2-85; UCH-L1 rises faster in females. Glial fibrillary acidic protein (GFAP) concentrations, indicating astrogliosis/inflammation, increase exponentially after age 40. Treatment with human granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim) halted neuronal cell death, as evidenced by reduced plasma UCH-L1 concentrations, in AD participants to levels equivalent to those of five-year-old healthy controls. The ability of GM-CSF treatment to reduce neuronal apoptosis was confirmed in a rat model of AD. These findings suggest that the exponential increase in neurodegeneration with age, accelerated by neuroinflammation, may underlie the contribution of aging to cognitive decline and AD and can be halted by GM-CSF/sargramostim treatment.