Brain Injury-Mediated Neuroinflammatory Response and Alzheimer's Disease

Abstract

Traumatic brain injury (TBI) is a major health problem in the United States, which affects about 1.7 million people each year. Glial cells, T-cells, and mast cells perform specific protective functions in different regions of the brain for the recovery of cognitive and motor functions after central nervous system (CNS) injuries including TBI. Chronic neuroinflammatory responses resulting in neuronal death and the accompanying stress following brain injury predisposes or accelerates the onset and progression of Alzheimer's disease (AD) in high-risk individuals. About 5.7 million Americans are currently living with AD. Immediately following brain injury, mast cells respond by releasing prestored and preactivated mediators and recruit immune cells to the CNS. Blood-brain barrier (BBB), tight junction and adherens junction proteins, neurovascular and gliovascular microstructural rearrangements, and dysfunction associated with increased trafficking of inflammatory mediators and inflammatory cells from the periphery across the BBB leads to increase in the chronic neuroinflammatory reactions following brain injury. In this review, we advance the hypothesis that neuroinflammatory responses resulting from mast cell activation along with the accompanying risk factors such as age, gender, food habits, emotional status, stress, allergic tendency, chronic inflammatory diseases, and certain drugs can accelerate brain injury-associated neuroinflammation, neurodegeneration, and AD pathogenesis.

Keywords: Alzheimer’s disease; blood-brain barrier; brain injury; neuroinflammation; traumatic brain injury.

Figure 1.

Acute neuroprotective immune response in the brain. Brain is not an immunologically privileged organ. Brain regions are continuously under surveillance by the innate immune cells to detect cell death, debris and infective organisms. Microglia are the resident innate immune cells that are neuroprotective (M2 phenotype) in the brain. Microglia are phagocytic and antigen presenting cells that release anti-inflammatory cytokines, chemokines and other mediators to maintain the brain homeostasis. Astrocytes (A2 phenotype) also play important role in neuroprotection by physically supporting the brain cells and BBB as well as by releasing neurotrophins and growth factors. Neutrophils infiltrate the site of infection or injury and further activate microglia and astrocytes in the brain. Mast cells are also necessary for brain development and neurobehavioral activities by releasing prestored and preactivated TNF-α and proteases within seconds followed by other neuroprotective cytokines and chemokines including IL-1α, IL-4, IL-10, IL-33, CCL2, TGF-β, histamine, tryptase and chymase. Mast cells are crucial in wound healing and tissue repair processes by promoting fibroblast growth, proliferation and its functions. Activated microglia and astrocytes release neuroprotective chemokines and cytokines within few hours whenever needed in the brain. These mediators induce recruitment of innate immune cells such as neutrophils and macrophages to the site of injury from the peripheral blood. The activated innate immune system protects the brain from further acute injury by removing dead cells and debris, initiating wound healing and axonal regrowth processes, neurodegeneration, fibrosis, protecting endothelial cells and BBB system in physiological conditions.

Figure 2.

Brain injury/TBI-mediated chronic neuroinflammatory response and neurodegeneration. Acute neuroprotective immune response fails to control the neuroinflammatory response if the brain injury is more and if the patient has other risk factor(s). Chronic immune response activates innate immune cells and microglia in the brain as well as in the peripheral system. Innate immune cells such as neutrophils, mast cells and some progenitor cells migrate from peripheral blood to the site of injury and further activate neuroglia and endothelial cells in the brain. Increased activation of microglia, macrophage, T-cells, astrocytes and mast cells increase the release of neuroinflammatory mediators such as CCL2, IL-1β, IL-6, IL-8, TNF-α, GM-CSF, VEGF, MMP-9, ROS and proteases with increased activation of NF-kB, AP-1, MAPKs, TREM2 and ApoE4 in the brain cells and immune cells. Brain injury increases M1 and A1 neurotoxic and proinflmmatory microglia and astrocytes respectively in the brain. High levels of these inflammatory mediators in the brain and in the peripheral blood causes chronic BBB and BCSFB dysfunctions, degeneration of pericytes and endothelial cells, neuroinflammation and neuronal death in vicious fashion that further leads to secondary damage in the brain. Several mast cell mediators including tryptase and chymase play a significant role in the BBB breach in neuroinflammation. TNF-α, tryptase, CCL2, VEGF, IL-1β, IL-6, IL-8, ROS and MMP-3 from activated mast cells contribute to the chronic neuroinflammation. Chronic neuroinflammation leads to neuronal death and initiates onset, progression and severity of AD in certain high-risk category people.

Figure 3.

Proposed brain injury/TBI-associated onset, progression and severity of AD in high-risk people. Brain injury leads to microbleeds and acute primary damage of brain cells. If acute immune response continues chronically, that leads to secondary damage of brain cells due to over activation of immune cells associated with s significantly higher levels of inflammatory and neurotoxic mediator release in a vicious fashion in the brain and peripheral immune system. Increased number of neurotoxic and inflammatory M1 microglia and A1 astrocytes exacerbates neuroinflammation and neurodegeneration in the injured brain. Normal aging process and brain injury generate APP and Aβ1–42 in the brain and these chronically activate neuroglia and immune cells in the brain that release several neuroinflammatory and neurotoxic mediators. Aβ and tau protein generate the formation of extracellular APs, and intracellular NFTs in the neurons, respectively. Immune system fails to remove the excess Aβ peptide and NFTs and thus the levels of these increases continuously. This is associated with the degeneration of pericytes and endothelial cells, increased neuroinflammation and neurodegeneration in the brain. This ultimately cause cognitive dysfunction and the onset of AD. Brain injury/TBI in high-risk people with PD, anxiety, depression, PTSD, CTE, ALS, aging, obesity, emotion, chronic peripheral diseases, chronic allergic tendencies, genetic factors, environmental factors, and high fat diet can accelerate the pathogenesis of AD.