Neuroinflammatory changes increase the impact of stressors on neuronal function

Abstract

In the last few years, several research groups have reported that neuroinflammation is one feature common to several neurodegenerative diseases and that similar, although perhaps less profound, neuroinflammatory changes also occur with age. Age is the greatest risk factor in many neurodegenerative diseases, and the possibility exists that the underlying age-related neuroinflammation may contribute to this increased risk. Several animal models have been used to examine this possibility, and it is now accepted that, under experimental conditions in which microglial activation is up-regulated, responses to stressors are exacerbated. In the present article, these findings are discussed and data are presented from in vitro and in vivo experiments which reveal that responses to Abeta (amyloid beta-peptide) are markedly up-regulated in the presence of LPS (lipopolysaccharide). These, and previous findings, point to a vulnerability associated with inflammation and suggest that, even though inflammation may not be the primary cause of neurodegenerative disease, its treatment may decelerate disease progression.

The Multifaceted Profile of Activated Microglia

“…While IL-1β has been shown to increase the synthesis [96] and processing [97] of amyloid precursor protein (APP) favoring the release of amyloid peptide fragments, Aβ stimulates microglial activation in vitro [29,41,98] and in vivo [29,[99][100][101][102] and this is accompanied by increased release of cytokines including IL-1β [29,100,102]. These findings suggest that a spiral of damaging events, involving accumulation of Aβ and microglial release of inflammatory molecules, may occur.…”

“…It increases release of IL-1β, IL-6, and TNF-α from cultured microglia, mixed glia, microglial cell lines [29,181,182], and monocytes [183]. Aβ synergizes with IFN-γ [184] and LPS [102] to stimulate production of proinflammatory cytokines. In human THP-1 monocytes, the evidence suggests that fibrillar Aβ, but not nonfibrillar Aβ, stimulates release of IL-1β [185]; the authors suggested that the response was triggered by a structural feature of the amyloid fibrils, possibly the cross β-fibril structure [185].…”

Age-related changes in the hippocampus (loss of synaptophysin and glial–synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL

“…Given the novel anti-inflammatory role of FGL, evidence indicating that FGL modulates glial cell activation (Downer et al 2010), and that maintenance of neuroglial cells in a non-inflammatory ('quiescent') state could be an important determining factor for preserving synaptic function (Piazza and Lynch, 2009), we wanted to investigate whether FGL directly affects glial-synaptic interaction at the EM level. Thus we proceeded to further determine the impact of aging and FGL treatment on neuroglial-synaptic interaction within the CA3-SR.…”

“…These changes are associated with an underlying neuroinflammatory response, typified by neuroglial activation and increased pro-inflammatory cytokine production (Godbout et al, 2005;Lyons et al, 2009). It has been proposed that the maintenance of neuroglial cells in a non-inflammatory ('quiescent') state could be an important determining factor for preserving synaptic function (Piazza and Lynch, 2009) minimizing the heightened vulnerability of the brain in aging.…”

Considerations and recent advances in neuroscience

“…On pp. xxx-xxx, Alessia Piazza and Marina Lynch explore one of the major factors associated with aging, namely neuroinflammation and how it relates to neurodegeneration and loss of synaptic function [1]. The main culprit in neuroinflammation is the activation of microglial cells which are the primary source of pro-inflammatory cytokines such as IL (interleukin)-1β.…”