The reason your three-pound brain doesn’t feel heavy is because it floats in a reservoir of cerebrospinal fluid (CSF) that flows in and around your brain and spinal cord. This fluid barrier between your brain and skull protects it from a blow to the head and washes your brain with nutrients.
But CSF has another, lesser-known critical function: it also provides immune protection to the brain. Still, this function is not well studied.
A Northwestern Medicine study of CSF discovered its role in cognitive disorders such as Alzheimer’s disease. This discovery provides a new clue to the neurodegeneration process, said lead author of the study, David Gate, assistant professor of neurology at Northwestern University Feinberg School of Medicine.
The study will be published on 13 December. Cell.
The study found that as people age, their CSF immune systems become dysregulated. The study also discovered that in people with cognitive impairment, such as those with Alzheimer’s disease, the CSF immune system is drastically different from healthy individuals.
“We’re now taking a look at the brain’s immune system with healthy aging and neurodegeneration,” Gate said. “This immune reservoir could potentially be used to treat brain inflammation or be used as a diagnostic to determine the level of brain inflammation in individuals with dementia.”
“We provide a comprehensive analysis of this important immunological repository of the healthy and diseased brain,” said Gate. His team shares the data publicly, and the results are searchable online.
To analyze CSF, Gate’s team at Northwestern used a sophisticated technique called single-cell RNA sequencing. By extracting CSF from the participants’ spines and isolating immune cells, they profiled 59 CSF immune systems of different ages.
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 these findings in the healthy group to CSF in 14 adults with cognitive impairment, as determined by their poor scores on memory tests.
Gate’s team of scientists observed genetic changes in CSF immune cells in healthy older individuals that cause cells to appear more active and inflamed with advanced age.
“Immune cells seem a little angry in older individuals,” Gate said. “We think this anger may make these cells less functional and cause the brain’s immune system to become dysregulated.”
In the cognitively impaired group, the inflammatory T cells cloned themselves and flowed into the CSF and the brain, as if following a radio signal, Gate said. The scientists found that cells have an excess of a cell receptor (CXCR6) that acts as an antenna. This receptor receives a signal – CXCL16 – to enter the brain from the degenerating brain’s microglia cells.
“The degenerating brain can activate these cells and cause them to clone themselves and flow into the brain,” Gate said. “They don’t belong there, and we’re trying to figure out if they’re contributing to the damage to the brain.”
Gate said that “his future goal is to block this radio signal or prevent the antenna from receiving the signal from the brain. We want to know what happens when these immune cells are blocked from entering the brain by neurodegeneration.”
Gate’s lab will continue to explore the role of these immune cells in brain diseases like Alzheimer’s. They also plan to spread to other diseases such as amyotrophic lateral sclerosis (ALS).
This work was supported in part by the National Institute on Aging (NIA) grant A R01AG078713-01, 10x Genomics Early Career Investigator Award, a National Institute of Neurological Disease and Stroke K99/R00 Pathway to Independence Award NS112458-01A1. NIA R01AG045034 05, NIA-funded Stanford ADRC P50AG047366 and P30AG066515, R01AG048076, all National Institutes of Health.
Other support was received from UC San Diego Shiley-Marcos grant ADRC P30 AG062429 and a pilot project through Northwestern University ADRC 1P30AG072977-01. Other support is from the Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging, the Cure Alzheimer’s Fund, the Alzheimer’s Association ADSF-21-818117 and NOMIS Foundation, NIA R01AG045034 05, NIA-funded Stanford ADRC P50AG047366 and P30AG066515, R01AG048076, UC taken. A pilot project through San Diego Shiley-Marcos ADRC P30 AG062429 and Northwestern University ADRC 1P30AG072977-01.