Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Abstract

Neuroinflammatory and neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

Keywords: Alzheimer’s disease; Gulf War Illness; Parkinson’s disease; human induced pluripotent stem cells; myalgic encephalomyelitis/chronic fatigue syndrome; neuroinflammation; traumatic brain injury.

Figure 1

Schematic diagram shows neuroimmune response, neuroinflammation, neurodegeneration and neuronal loss in AD. AD pathogenesis involves neuroimmune response and is associated with the formation of APs and NFTs leading to chronic neuroinflammation, BBB disruption, synaptic loss and neuronal damage in the brain. Chronic activation of astrocytes and microglia release several proinflammatory cytokines, chemokines and neurotoxic mediators (ROS, NO) that further activate glial cells and neurons and induce neuronal death. Molecules released from dying neurons such as DAMPs, S100β, etc. further activate glial cells. Inflammatory cytokines and chemokines from the periphery could enter the brain through damaged BBB and increase neuroinflammation and neurodegeneration. Iba1 = Ionized calcium binding adaptor molecule 1; DAMPS = damage-associated molecular patterns; GFAP = Glial fibrillary acidic protein; NO = nitric oxide; P2Y12R = P2Y12 receptor; ROS = reactive oxygen species; TMEM119 = transmembrane protein 119.

Figure 2

Schematic illustration depicts neuroinflammatory processes in the pathogenesis of TBI. TBI-induced immune response activates microglia, astrocytes and immune cells in the brain, and releases neurotoxic proinflammatory cytokines and chemokines, leading to neuroinflammation, BBB disruption and neuronal death. Primary damage directly causes neuronal injury, whereas secondary brain damage is due to the neuroinflammatory processes following TBI. Inflammatory mediators released from activated glial cells further activate glial cells and release additional neuroinflammatory molecules leading to neuroinflammation, BBB disruption, neurodegeneration and neuronal death. NfL and UCH-L1 are released from damaged neurons and GFAP and S100B are released from activated and damaged astrocytes. NfL, UCH-L1, GFAP and S100B released from brain cells enter into the blood through damaged BBB. BBB = blood–brain barrier; GFAP = glial fibrillary acidic protein; ICAM-1 = intercellular adhesion molecule-1; UCH-L1 = ubiquitin C-terminal hydrolase L1; VCAM-1 = vascular adhesion molecule-1.

Figure 3

Graphical diagram of the derivation, differentiation, and potential applications of human iPSC in neuroinflammatory disease pathogenesis and therapeutics. iPSCs are derived from somatic cells isolated from patients or healthy donors by reprogramming. CRISPR/Cas9-mediated gene editing is used to correct or introduce the mutation to generate isogenic iPSCs. They can be differentiated into neural precursors using dual SMAD inhibition-based protocols and cultured in monolayer (2D) or in 3D as organoids. Specific morphogens are applied directing the differentiation to the desired cell fate. These disease-relevant cell types including neurons, oligodendrocytes, astrocytes, microglia, pericytes and vascular endothelial cells differentiated from iPSC either patient-derived or isogenic have potential applications in regenerative medicine and disease therapeutics. AD = Alzheimer’s disease; ALS = amyotrophic lateral sclerosis; GWI = Gulf War Illness; iPSC = induced pluripotent stem cells; ME/CFS = myalgic encephalomyelitis/chronic fatigue syndrome; PD = Parkinson’s disease; TBI = traumatic brain injury.