Chapter 95
Neurodegeneration — 1
In recent years, a revolution occurred in our understanding of immunity and the brain. For more than a century, the medical dogma was that the brain was “immune-privileged” in a separate compartment, isolated from and inaccessible to the body’s immune system. But in the 1990s, initial evidence of T cells entering healthy brains was found.
That was a first step toward realizing that there is a brain lymphatic system (known as the glymphatic system) that communicates with the rest of the body, and that the skull bone marrow, meninges (membrane layers that cover the brain), and choroid plexus are an immune cell reservoir—a squad of immune cells that patrol the brain from its border, traversing in through and alongside vascular channels, cerebrospinal fluid, and specialized lymphatics. Triggered by synchronized brain cell firing, clearance of metabolic waste occurs through the glymphatic system plumbing—or, in the more colloquial term, brainwashing. Skull-meninges channels allow immune cells to flow back and forth without any need of blood vessels. In neurodegenerative diseases, the brain’s immune cell system plays a major role with prominent involvement of CD4+ (helper), CD8+ (cytotoxic), NK cells, white blood cells, and monocytes. That role can range from helping to protect against degenerative changes, fighting brain cancer, to activating inflammation with pro-inflammatory effects.
Within the brain there is one type of cell that serves as a key player interacting with the immune response—the microglia, a specialized form of macrophage cells. As molecular pharmacologist Giulia Castellani wrote in a recent review in Science: “In adulthood, the microglia serve as the sentinels of the brain.” They accumulate lipid droplets and release pro-inflammatory cytokines; they gradually lose their mobility and ability to perform their housekeeping function. This can all result in a disruption of the blood-brain barrier. Moreover, exhausted, “terminally inflammatory” microglia appear to contribute to the loss of synapses and the risk of neurodegenerative disease. Microglia interact with astrocyte cells, which can become active participants in neuroinflammation and are linked to brain cell death. Preventing neurodegenerative diseases is dependent, at least in part, on maintaining a healthy relationship between the brain tissue and immune system, with microglia serving as a gateway to their interaction.
There are several hallmarks of neurodegenerative diseases, including a buildup of misfolded proteins, inflammation, brain cell death, defects in DNA and RNA, and synaptic dysfunction.
Our brain structurally changes considerably as we age, even without exhibiting dysfunctional or degenerative features. In 2023, a large international collaboration, led by Richard Bethlehem and Jacob Seidlitz, reported a massive study of about 124,000 MRI scans from over 101,000 people, aged four months to one hundred years of age. This landmark paper enlightened the major dynamic structural changes as we age. White matter, gray matter, and cortical thickness (corresponding to the width of gray matter) are shrinking, whereas, in late adulthood, the volume of cerebrospinal fluid in the brain is sharply increasing. The exponential increase in ventricular volume, beginning at about forty years of age, is seen in figure 7.1.
The functional correlations for these structural changes are still being determined, but what we have now is a growth chart, just like what is routinely used in children, to be able to say what is normal or abnormal at different points over time. While these changes are at the macro level, there is single-cell and spatial omic characterization of the brain at the cellular and molecular levels.