Neuron Death in the Brain Occurs Throughout Life, But Increases with Age
Damaged and dying neurons in the brain release distinctive proteins that make their way into the bloodstream and can thus be measured. Researchers here note that by this metric, the death of neurons occurs throughout life, but increases with age. The pace of neuron death further increases in patients with neurodegenerative conditions, as might be expected. Interestingly, the established treatment of recombinant GM-CSF protein is shown to greatly reduce this age-related increase in neuron death. Recombinant protein therapies are notably costly and the effects of a single dose typically do not last long, but perhaps more attention given to this mechanism will lead to a more cost effective approach to therapy that can preserve neurons in the aging brain.
A new cross-sectional study of people of all ages has revealed that a protein released into the blood from dying brain neurons, called UCH-L1, and another protein released from damaged neurons, called NfL, are at low concentrations in the blood in early life and their levels are exponentially higher every year through age 85. Early life changes in this biomarker likely reflect a normal process of aging, but in later stages of life, increases in UCHL-1 are linked with poorer outcomes. This discovery could lead to earlier testing and new therapies for Alzheimer's disease (AD) and possibly for cognitive decline due to normal aging.
The drug sargramostim (also called Leukine), a synthetic form of the natural human protein GM-CSF, has been used for 30 years to treat a variety of conditions including cancer. It has also shown promise in its first clinical trial by improving blood biomarkers of brain pathology. The biomarker improvement lasted only as long as the drug was taken, yet memory improvement on one measure lasted longer. When people with AD were given sargramostim in the clinical trial, their blood levels of the UCH-L1 measure of neuronal cell death dropped by 40%, similar to levels seen in early life.
Sargramostim treatment led to improved scores on one of the cognitive tests performed, the Mini-Mental State Exam (MMSE), compared to those taking a placebo. Other cognitive tests showed no change. Whether the drug will reduce Alzheimer-associated neuronal damage only with continuous use is unclear and needs more study. At 45 days after treatment ended, the blood UCH-L1 concentration had returned to pre-treatment levels but the improvement in the MMSE measure of cognition was retained. More research will also be needed to determine if the drug can reduce normal age-associated neuron death and cognitive decline.