Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer's Disease

Abstract

Mast cell activation plays an important role in stress-mediated disease pathogenesis. Chronic stress cause or exacerbate aging and age-dependent neurodegenerative diseases. The severity of inflammatory diseases is worsened by the stress. Mast cell activation-dependent inflammatory mediators augment stress associated pain and neuroinflammation. Stress is the second most common trigger of headache due to mast cell activation. Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disease that affects more women than men and woman's increased susceptibility to chronic stress could increase the risk for AD. Modern life-related stress, social stress, isolation stress, restraint stress, early life stress are associated with an increased level of neurotoxic beta amyloid (Aβ) peptide. Stress increases cognitive dysfunction, generates amyloid precursor protein (APP), hyperphosphorylated tau, neurofibrillary tangles (NFTs), and amyloid plaques (APs) in the brain. Stress-induced Aβ persists for years and generates APs even several years after the stress exposure. Stress activates hypothalamic-pituitary adrenal (HPA) axis and releases corticotropin-releasing hormone (CRH) from hypothalamus and in peripheral system, which increases the formation of Aβ, tau hyperphosphorylation, and blood-brain barrier (BBB) disruption in the brain. Mast cells are implicated in nociception and pain. Mast cells are the source and target of CRH and other neuropeptides that mediate neuroinflammation. Microglia express receptor for CRH that mediate neurodegeneration in AD. However, the exact mechanisms of how stress-mediated mast cell activation contribute to the pathogenesis of AD remains elusive. This mini-review highlights the possible role of stress and mast cell activation in neuroinflammation, BBB, and tight junction disruption and AD pathogenesis.

Keywords: Alzheimer’s disease; amyloid plaques; chronic stress; corticotropin releasing hormone; mast cells; neurodegenerative disease; neuroinflammation.

FIGURE 1

Schematic diagram shows bidirectional communications between nociceptor neuron and mast cells during pain and inflammation. Mast cells are located close to nociceptor/neurons. Several conditions activate mast cells to release preformed preactivated and granule stored neuroactive inflammatory mediators and growth factors by degranulation or release many newly synthesized neuroactive and neuroinflammatory mediators. Mast cells express several receptors including CRHR, NK1, S1P1, and S1P2 for the mediators released from the neurons and for the cytokines/chemokines and various growth factors. Similarly, nociceptor neurons also express receptors including PAR-2, TNF-R, IL-1R, histamine R1/2, and NK-1for mast cell released mediators. Histamine, serotonin, and prostaglandins released from mast cells induce pain signals. Mast cell-released inflammatory mediators and growth factors induce pain signals and inflammation in many neuroinflammatory and neurodegenerative diseases. CRHR, corticotropin-releasing hormone receptor; IL-1R, IL-1 receptor; NK-1, neurokinin-1; NGF, nerve growth factor; PAR-2, protease-activated receptor-2; S1P, sphingosine-1 phosphate; TNFR, TNF receptor; TrkA, Tropomyosin receptor kinase A.

FIGURE 2

Diagram showing stress can exacerbate neuroinflammation and neurodegeneration and accelerates the pathogenesis of AD. Various chronic stress and acute stress conditions differentially activates hypothalamus and release CRH in the brain. Stress also activates immune and inflammatory response in the brain that leads to the activation of immune and inflammatory cells, and glia associated with neuroinflammatory mediator release and pain. Stress increases the generation of APP, Aβ, hyperphosphorylated tau, induces cognitive disorders, reduce brain volume, decrease growth factor expression, increases oxidative stress, and activates mast cells and neuroglia. Several mast cell-derived inflammatory mediators induce severe migraine/headache in stress conditions. Stress affects BBB functions, induces tight junction damage and tight junction protein rearrangements. Chronic stress can shorten the duration to develop AD and dementia and increases its severity. APP, amyloid precursor protein; Aβ, beta amyloid; BBB, blood-brain barrier; GLUT-1, glucose transporter-1; IL, interleukin; NFTs, GVU, gliovascular unit; neurofibrillary tangles; NT, neurotensin; NVU, neurovascular unit; ZO, zonula occluden; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1.