Glial‐Neuronal Interactions in Alzheimer's Disease: The Potential Role of a ‘Cytokine Cycle’ in Disease Progression

Abstract

The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the ␤-amyloid precursor protein, thus favoring continuing deposition of ␤-amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100␤, is a neurite growth-promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine-induced neuronal insults can activate microglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…In the brains of both AD individuals and transgenic animal models, it was found that Ab plaques are surrounded by activated glial cells (Bauer et al 1991;Cagnin et al 2001;Fillit et al 1991;Liu et al 2013;Varnum and Ikezu 2012). Activated microglia and astrocytes strongly secrete inflammatory components such as pro-inflammatory cytokines, chemokines, complement, macrophage inflammatory proteins, monocyte chemoattractant proteins, reactive oxygen species (ROS), nitric oxide (NO) prostaglandins, leukotrienes, thromboxanes and so on (Akiyama et al 2000;Griffin et al 1998;Mrak et al 1995;Town et al 2005;Tuppo and Arias 2005). The released inflammatory molecules, especially some cytokines such as interleukin (IL)-18, IL-1b and tumor necrosis factor (TNF)-a, impair the balance of normal neurophysiologic condition that correlates with cognition and learning and memory (Fillit et al 1991;Gemma and Bickford 2007;Jankowsky and Patterson 1999;Liu et al 2013;Varnum and Ikezu 2012).…”

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

“…Evidence indicates that astrocytes beneficially contribute to clearance of accumulated Aβ [109,110], but also contribute to inflammatoryinduced neuronal damage such as by producing neurotoxic nitric oxide [111] and cytokines. Activated microglia also release inflammatory cytokines and nitric oxide, as well as reactive oxygen species, and activate the complement system [112]. Thus, on one hand, these inflammatory molecules produced by glia cells are thought to contribute to the pathological progression of AD, while on the other hand, by contributing to the clearance of Aβ and secreting growth factors, both activated astrocytes and microglia are not thought to be entirely detrimental in AD [113,114].…”

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

“…inflammatory response in the brain that exceeds early neuroprotection and results in neurodegenerative changes capable of continuing the inflammatory cycle. 9,27,90 Chronic inflammation has been observed in a number of studies examining patients with trauma-related anxiety disorders, reporting increases in downstream mediators, such as peripheral elevations of TNF-a, interferon-gamma (IFN-c), IL-1b, and IL-6, in patients with PTSD, [13][14][15][16] elevations of TNF-a and IL-6 in patients with OCD, 17 and elevations in proinflammatory cytokines and chemokines (monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, IL-1a, IL-1b, IL-6, IL-8, Eotaxin, granulocyte macrophage colony-stimulating factor, and IFN-c) in individuals with panic disorder and PTSD. 18 Despite compelling evidence implicating excessive inflammatory actions and a generalized inflammatory state in the development of anxiety disorders after TBI, central measures of proinflammatory cytokine elevations specifically related to human PTSD and other anxiety disorders have not yet been performed.…”