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Review
. 2011 May;10(3):391-403.
doi: 10.2174/187152711794653751.

Targeting TNF-α to Elucidate and Ameliorate Neuroinflammation in Neurodegenerative Diseases

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Free PMC article
Review

Targeting TNF-α to Elucidate and Ameliorate Neuroinflammation in Neurodegenerative Diseases

Kathryn A Frankola et al. CNS Neurol Disord Drug Targets. .
Free PMC article

Abstract

Inflammatory signals generated within the brain and peripheral nervous system direct diverse biological processes. Key amongst the inflammatory molecules is tumor necrosis factor-α (TNF-α), a potent pro-inflammatory cytokine that, via binding to its associated receptors, is considered to be a master regulator of cellular cascades that control a number of diverse processes coupled to cell viability, gene expression, synaptic integrity and ion homeostasis. Whereas a self-limiting neuroinflammatory response generally results in the resolution of an intrinsically or extrinsically triggered insult by the elimination of toxic material or injured tissue to restore brain homeostasis and function, in the event of an unregulated reaction, where the immune response persists, inappropriate chronic neuroinflammation can ensue. Uncontrolled neuroinflammatory activity can induce cellular dysfunction and demise, and lead to a self-propagating cascade of harmful pathogenic events. Such chronic neuroinflammation is a typical feature across a range of debilitating common neurodegenerative diseases, epitomized by Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, in which TNF-α expression appears to be upregulated and may represent a valuable target for intervention. Elaboration of the protective homeostasis signaling cascades from the harmful pathogenic ones that likely drive disease onset and progression could aid in the clinical translation of approaches to lower brain and peripheral nervous system TNF-α levels, and amelioration of inappropriate neuroinflammation.

Figures

Figure 1
Figure 1. Microglial Cells
Microglia are the resident macrophage-like cell in brain. They respond to various stimuli in their microenvironment, such as Aβ, α-synuclein, oxidative stress and pathogens, by undergoing morphological changes from a ramified – resting state to an ameboid – activated state. When microglia become activated they respond by synthesizing an array of soluble factors (TNF-α, IL-1 α/β, INFγ and reactive oxygen species). These factors can (1) induce resting cells to become activated cells or (2) they may damage functional neurons leading to the generation of dysfunctional neurons. In several central nervous system diseases conditions exist that allow for the formation of a TNF-α-mediated feed back loop of self-activating neuroinflammation.
Figure 2
Figure 2. TNF-α signaling
TNF-α can bind with either of its receptors and initiate several pathways: activation of NFκB dependent signaling can lead to beneficial effects [138, 139]. Activation of c-Jun N-terminal kinase (JNK) pathway may lead to either beneficial or harmful effects [170]. The activation of caspase dependent signaling typically leads to apoptotic mediated cell death in neurons [171].

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