The reason your three-pound brain doesn’t feel heavy is because it floats in a reservoir of cerebrospinal fluid (CSF), which flows in and around your brain and spinal cord. This liquid barrier between the brain and the skull protects it from a blow to the head and bathes the brain in nutrients.
But the CSF has another critical, albeit less well understood, function: it also provides immune protection to the brain. However, this function has not been well studied.
A Northwestern Medicine study on CSF has discovered its role in cognitive decline, such as Alzheimer’s disease. This discovery provides a new clue into the process of neurodegeneration, said the study’s lead author, David Gate, an assistant professor of neurology at Northwestern University Feinberg School of Medicine.
The study will be published on December 13 in Cell.
The study found that as people age, their CSF immune system becomes dysregulated. In people with cognitive impairment, such as those with Alzheimer’s disease, the CSF immune system is drastically different from that of healthy people, the study also found.
“Now we can glimpse the brain’s immune system with healthy aging and neurodegeneration,” Gate said. “This immune reservoir could potentially be used to treat inflammation of the brain or used diagnostically to determine the level of brain inflammation in people with dementia.”
“We offer a comprehensive analysis of this important immune reservoir of the healthy and diseased brain,” Gate said. Her team is sharing the data publicly and their results are searchable online.
To analyze the CSF, Gate’s team at Northwestern used a sophisticated technique called single-cell RNA sequencing. They profiled 59 CSF immune systems across a spectrum of ages by taking CSF from the participants’ spinal cord and isolating their immune cells.
The first part of the study analyzed CSF in 45 healthy individuals aged 54 to 83 years. The second part of the study compared those findings in the healthy group with CSF in 14 cognitively impaired adults, as determined by their low scores on memory tests.
Gate’s team of scientists observed genetic changes in CSF immune cells in healthy older individuals that made the cells appear more activated and inflamed with advancing age.
“Immune cells seem to be a bit angry in older people,” Gate said. “We think this anger could make these cells less functional, resulting in dysregulation of the brain’s immune system.”
In the cognitively impaired group, the inflamed T cells were cloned and flowed into the CSF and brain as if they were following a radio signal, Gate said. The scientists found that the cells had an excess of a cellular receptor, CXCR6, which acts like an antenna. This receptor receives a signal, CXCL16, from degenerating brain microglia cells to enter the brain.
“It could be that the degenerating brain activates these cells and causes them to clone and flow into the brain,” Gate said. “They don’t belong there and we are trying to understand if they contribute to damage in the brain.”
Gate said his “future goal is to either block that radio signal, or prevent the antenna from receiving that signal from the brain. We want to know what happens when these immune cells can’t get into the brain with neurodegeneration.”
Gate’s lab will continue to explore the role of these immune cells in brain diseases such as Alzheimer’s. They also plan to expand to other diseases, such as amyotrophic lateral sclerosis (ALS).
This work was supported in part by a grant A R01AG078713-01 from the National Institute on Aging (NIA), a 10x Genomics Early Career Investigator Award, a Pathway to Independence Award NS112458-01A1 from the National Institute of Neurological Diseases and Stroke K99 /R00, NIA R01AG045034 05, NIA funded Stanford ADRC P50AG047366 and P30AG066515, R01AG048076, all National Institutes of Health.
Other support was from UC San Diego Shiley-Marcos ADRC grant P30 AG062429, and a pilot project through Northwestern University ADRC 1P30AG072977-01. Other support was from the Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging, Cure Alzheimer’s Fund, Alzheimer’s Association ADSF-21-818117 and NOMIS Foundation, NIA R01AG045034 05, Stanford ADRC-funded NIA P50AG047366 and P30AG066515, R01AG048076, UC San Diego Shiley- Mark ADRC P30 AG062429, and a pilot project through Northwestern University ADRC 1P30AG072977-01.