Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer's disease

Abstract

Neuroinflammation is instigated by the misfiring of immune cells in the central nervous system (CNS) involving microglia and astrocytes as key cell-types. Neuroinflammation is a consequence of CNS injury, infection, toxicity, or autoimmunity. It is favorable as well as a detrimental process for neurodevelopment and associated processes. Transient activation of inflammatory response involving release of cytokines and growth factors positively affects the development and post-injury tissue. However, chronic or uncontrolled inflammatory responses may lead to various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, and multiple sclerosis. These diseases have variable clinical and pathological features, but are underlaid by the aggregation of misfolded proteins with a cytotoxic effect. Notably, abnormal activation of glial cells could mediate neuroinflammation, leading to the neurodegenerative condition. Microglia, a type of glial cell, a resident immune cell, form the forefront defense of the CNS immune system. Dysfunctional microglia and astrocyte, a different kind of glial cell with homeostatic function, impairs the protein aggregate (amyloid-beta plaque) clearance in AD. Studies have shown that microglia and astrocytes undergo alterations in their genetic profile, cellular and molecular responses, and thus promote dysfunctional immune cross-talk in AD. Hence, targeting microglia and astrocytes-driven molecular pathways could resolve the particular layers of neuroinflammation and set a reliable therapeutic intervention in AD progression.

Keywords: Alzheimer’s disease; Amyloid beta; Astrocytes; Microglia; Neuroinflammation.

Fig. 1

Schematic showing the modes of neuroinflammation in healthy and AD brain. A The healthy brain has minimal Aβ aggregates. Under normal physiological function microglia and astrocytes maintain neuronal homeostasis by clearing Aβ aggregates and providing neurotrophic factor to the brain. B The Alzheimer’s brain is associated with a large number of Aβ aggregates. The inhibited phagocytosis of Aβ aggregates and abrupt inflammatory response by microglia and astrocytes lead to the Aβ aggregates accumulation. Aβ aggregates bind to the pattern recognition receptors (PRRs) of microglia and stimulate downstream target genes NF-κB and AP-1. Subsequently, activated microglia produces cytokines. Cytokines contribute to astrocytes activation (referred to as reactive astrocytes) and affect neuronal health by causing neurotoxicity. The binding of Aβ aggregates to the microglia induces the NADPH oxidase and inducible nitric oxide synthase to produce ROS and NO leading to neurotoxicity. Likewise, Aβ aggregates bind to astrocyte receptors leading to the activation of downstream target genes NF-κB and AP-1 that subsequently produce cytokines. Cytokines affect neuronal health and cause neurotoxicity. The Aβ aggregates induce NADPH oxidase and inducible nitric oxide to produce ROS and NO by reactive astrocytes. The abrupt cross-talk between neurons, astrocytes, and microglia involving inflammatory molecules shown in the picture causes an imbalance in brain homeostasis and promotes neuronal death