How the immune system shapes neurodegenerative diseases

Abstract

Neurodegenerative diseases are a major cause of death and disability worldwide and are influenced by many factors including age, genetics, and injuries. While these diseases are often thought to result from the accumulation and spread of aberrant proteins, recent studies have demonstrated that they can be shaped by the innate and adaptive immune system. Resident myeloid cells typically mount a sustained response to the degenerating CNS, but peripheral leukocytes such as T and B cells can also alter disease trajectories. Here, we review the sometimes-dichotomous roles played by immune cells during neurodegenerative diseases and explore how brain trauma can serve as a disease initiator or accelerant. We also offer insights into how failure to properly resolve a CNS injury might promote the development of a neurodegenerative disease.

Keywords: adaptive immunity; brain injury; innate immunity; neurodegeneration.

Figure 1.. The innate and adaptive immune reaction neurodegeneration.

Neurodegenerative diseases are marked by cortical atrophy and the accumulation of aberrant proteins inside and outside CNS cells. Aberrant proteins distress neurons, contributing to their death and subsequent cortical atrophy. This initially triggers and innate immune reaction in the CNS that can lead to engagement of adaptive immune cells such as CD8⁺ T cells, CD4⁺ T cells, and B cells. Within the CNS parenchyma microglia and astrocytes become reactive and acquire new functional properties. These cells are sometimes referred to as disease-associated microglia (DAM) and disease-associated astrocytes (DAA), respectively. The reactive microglia and astrocytes often attempt to contain the spread of aberrant proteins and aid distressed neurons. They also release cytokines and chemokines that facilitate recruitment of T and B cells from circulation. CD8⁺ T cells have been observed engaging both neurons and microglia during neurodegenerative diseases, suggesting that the participate in removing these two cell populations. CD4⁺ T cells also interact with microglia and possibly neurons during neurodegenerative diseases. The role B cells is not entirely clear, but these cells have the potential to influence the course of disease by producing antibodies against aberrant proteins and/or releasing immunoregulatory cytokines.

Figure 2.. Immune Response to Brain Injury.

(A) The normal anatomy of the meninges (dura mater, arachnoid mater, pia mater) and superficial neocortex is depicted. During steady state, the meninges are surveyed primarily by meningeal macrophages. These cells are dynamic and reside mostly in the dura mater. Beneath the glia limitans superficialis, which is comprised of surface associated astrocytes, the brain parenchyma is surveyed by microglia. (B) Mild traumatic brain injuries (mTBI) often cause meningeal damage, resulting in vascular leakage and death of meningeal macrophages, endothelial cells, and other meningeal residents. Astrocytes along the glia limitans superficialis can also become distressed or damaged. Part of their damage response includes release of ATP via connexin hemichannels into the underlying brain parenchyma. This causes microglia to extend processes in a purinergic receptor dependent manner to the glial limitans. These reactive microglia help seal the glia limitans barrier and limit the degree of leak into the brain parenchyma. When astrocytes die, microglia transform into a jellyfish-like, amoeboid morphology and begin clearing debris. A major source of cellular and barrier damage following a single mTBI are reactive oxygen species (ROS), which are released into the meningeal space. A second mTBI can significantly enhance the amount of meningeal and parenchymal damage by increasing ROS concentrations. For example, a second injury encountered within a day of the first causes rapid death of barrier supportive microglia, resulting in increased leakage of the glia limitans superficialis. Myelomonocytic cells from circulation also massively invade the damaged meninges after a second injury and even enter the brain parenchyma by traversing the damaged glia limitans superficialis. Importantly, transcranial or intravenous delivery of the free radical scavenger, glutathione, can be used therapeutically to lessen cellular damage (both in the meninges and parenchyma), glia limitans breakdown, and inflammation following single or repetitive mTBI (not depicted). (C) Cerebrovascular injuries resulting from a stroke, intracerebral hemorrhage or TBI are often associated with the leakage of water (edema) and / or red blood cells into the brain parenchyma. This causes distressed astrocytes comprising the BBB to release ATP via connexin hemichannels. Microglia respond to this ATP within minutes using purinergic receptors and project barrier sealing processes that wrap the damaged blood vessel(s). Failure microglia to wrap these blood vessels results in more extensive vascular leakage and secondary parenchyma damage. Myelomonocytic cells can also be massively recruited from circulation following cerebrovascular injury. These cells are required at later stages for vascular repair but can acutely increase brain swelling (within the first 12 hours of injury) by promoting the entry of water into the brain while extravasating.

Figure 3.. Induction of neurodegeneration by repetitive brain Injury.

(A) The normal anatomy of the meninges and superficial neocortex is depicted with a blood vessel traversing the pia mater and entering the brain. (B) Repeated brain injuries can induce neurodegenerative processes by promoting leaky CNS barriers. Exposure of the meninges and brain to multiple injuries can lead to chronic vascular leakage and disruption of the glia limitans superficialis and perivascularis. Continual leakage of materials from the blood and CSF into the parenchyma can contribute to neural disequilibrium and dysfunction. Microglia and astrocytes in areas of repetitive brain damage often assume a reactive state, and astrocytes are sometimes observed forming a scar along the damaged glia limitans. Repetitive brain injuries can also lead to the deposition of aberrant proteins like pTau both inside and outside of neurons. This can trigger a microglial response and recruitment of peripheral immune cells.