Study Implicates Cerebrospinal Fluid Dysregulation in Alzheimer’s

Researchers from Northwestern University report that dysregulation of cerebrospinal fluid (CSF) as we age contributes to cognitive impairment—findings that expand understanding of neurodegeneration and could be used to treat inflammation of the brain.

CSF is a liquid barrier in and around the brain and spinal cord that protects against injury and provides nutrients and immune protection. The study found that people with cognitive impairment, such as those with Alzheimer’s disease, exhibit a CSF immune system drastically different from healthy individuals.

“We now have a glimpse into the brain’s immune system with healthy aging and neurodegeneration,” says lead author David Gate, assistant professor of neurology at Northwestern University Feinberg School of Medicine. “This immune reservoir could potentially be used to treat inflammation of the brain or be used as a diagnostic to determine the level of brain inflammation in individuals with dementia.”

Gate and colleagues used single-cell RNA sequencing to profile 59 CSF immune systems from a spectrum of ages by taking CSF from participants’ spines and isolating their immune cells.

The first part of the study looked at CSF in 45 healthy individuals aged 54 to 83 years. The second part of the study compared those findings in the healthy group to CSF in 14 adults with cognitive impairment, as determined by their poor scores on memory tests.

The team observed genetic changes in the CSF immune cells in older healthy individuals that made the cells appear more activated and inflamed with advanced age. “The immune cells appear to be a little angry in older individuals,” Gate says. “We think this anger might make these cells less functional, resulting in dysregulation of the brain’s immune system.”

In the cognitively impaired group, inflamed T-cells cloned themselves and flowed into the CSF and brain as if they were following a radio signal, Gate said. Scientists found the cells had an overabundance of a cell receptor—CXCR6—that acts as an antenna. This receptor receives a signal—CXCL16—from the degenerating brain’s microglia cells to enter the brain.

“It could be the degenerating brain activates these cells and causes them to clone themselves and flow to the brain,” Gate says. “They do not belong there, and we are trying to understand whether they contribute to damage in the brain.”

Future work includes blocking this “radio signal” or inhibiting “the antenna” from receiving the signal from the brain, Gate says. “We want to know what happens when these immune cells are blocked from entering brains with neurodegeneration.”

The findings were published recently in the journal Cell.