Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease

Fiona E McAlpine, Malú G TanseyAbstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects nearly one in two individuals over 90 years of age. Its neuropathological hallmarks are accumulation of extraneuronal plaques of amyloid-beta (A&...

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Autores principales: Fiona E McAlpine, Malú G Tansey
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Lenguaje:EN
Publicado: Dove Medical Press 2008
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spelling oai:doaj.org-article:dcf27232b0da4b88bbc89cfb1d62d5242021-12-02T02:48:18ZNeuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease1178-7031https://doaj.org/article/dcf27232b0da4b88bbc89cfb1d62d5242008-11-01T00:00:00Zhttp://www.dovepress.com/neuroinflammation-and-tumor-necrosis-factor-signaling-in-the-pathophys-a2551https://doaj.org/toc/1178-7031Fiona E McAlpine, Malú G TanseyAbstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects nearly one in two individuals over 90 years of age. Its neuropathological hallmarks are accumulation of extraneuronal plaques of amyloid-beta (Aβ), the presence of neurofibrillary tangles formed by aberrantly hyperphosphorylated tau, progressive synaptic loss, and neurodegeneration which eventually results in decline of memory and cognitive faculties. Although the etiology of sporadic AD in humans is unknown, mutations in amyloid precursor protein or components of its processing machinery (β-secretase and γ-secretase) result in overproduction of Aβ1–40 and 1–42 peptides and are sufficient to cause disease. In this review, we highlight the experimental and clinical evidence that suggests a close association between neuroinflammation and AD pathogenesis. Overproduction of inflammatory mediators in the brain occurs when microglia, which are often found in close physical association with amyloid plaques in AD brains, become chronically activated. It has been proposed that elevated levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF), may inhibit phagocytosis of Aβ in AD brains thereby hindering efficient plaque removal by resident microglia. In support of this idea, the bacterial endotoxin lipopolysaccharide, a potent trigger of inflammation that elicits production of TNF and many other cytokines, can accelerate the appearance and severity of AD pathology in several animal models of AD. We review the evidence implicating TNF signaling in AD pathology and discuss how TNF-dependent processes may contribute to cognitive dysfunction and accelerated progression of AD. We conclude by reviewing the observations that provide compelling rationale to investigate the extent to which new therapeutic approaches that selectively target the TNF pathway modify progression of neuropathology in pre-clinical models of AD as well as the promising findings with the use of nonsteroidal anti-inflammatory drugs and recent clinical trials with Aβ immunotherapy.Keywords: neuroinflammation, tumor necrosis factor, microglia, neurodegeneration, Alzheimer’s disease Fiona E McAlpineMalú G TanseyDove Medical PressarticlePathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol 2008, Iss default, Pp 29-39 (2008)
institution DOAJ
collection DOAJ
language EN
topic Pathology
RB1-214
Therapeutics. Pharmacology
RM1-950
spellingShingle Pathology
RB1-214
Therapeutics. Pharmacology
RM1-950
Fiona E McAlpine
Malú G Tansey
Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease
description Fiona E McAlpine, Malú G TanseyAbstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects nearly one in two individuals over 90 years of age. Its neuropathological hallmarks are accumulation of extraneuronal plaques of amyloid-beta (Aβ), the presence of neurofibrillary tangles formed by aberrantly hyperphosphorylated tau, progressive synaptic loss, and neurodegeneration which eventually results in decline of memory and cognitive faculties. Although the etiology of sporadic AD in humans is unknown, mutations in amyloid precursor protein or components of its processing machinery (β-secretase and γ-secretase) result in overproduction of Aβ1–40 and 1–42 peptides and are sufficient to cause disease. In this review, we highlight the experimental and clinical evidence that suggests a close association between neuroinflammation and AD pathogenesis. Overproduction of inflammatory mediators in the brain occurs when microglia, which are often found in close physical association with amyloid plaques in AD brains, become chronically activated. It has been proposed that elevated levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF), may inhibit phagocytosis of Aβ in AD brains thereby hindering efficient plaque removal by resident microglia. In support of this idea, the bacterial endotoxin lipopolysaccharide, a potent trigger of inflammation that elicits production of TNF and many other cytokines, can accelerate the appearance and severity of AD pathology in several animal models of AD. We review the evidence implicating TNF signaling in AD pathology and discuss how TNF-dependent processes may contribute to cognitive dysfunction and accelerated progression of AD. We conclude by reviewing the observations that provide compelling rationale to investigate the extent to which new therapeutic approaches that selectively target the TNF pathway modify progression of neuropathology in pre-clinical models of AD as well as the promising findings with the use of nonsteroidal anti-inflammatory drugs and recent clinical trials with Aβ immunotherapy.Keywords: neuroinflammation, tumor necrosis factor, microglia, neurodegeneration, Alzheimer’s disease
format article
author Fiona E McAlpine
Malú G Tansey
author_facet Fiona E McAlpine
Malú G Tansey
author_sort Fiona E McAlpine
title Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease
title_short Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease
title_full Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease
title_fullStr Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease
title_full_unstemmed Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease
title_sort neuroinflammation and tumor necrosis factor signaling in the pathophysiology of alzheimer’s disease
publisher Dove Medical Press
publishDate 2008
url https://doaj.org/article/dcf27232b0da4b88bbc89cfb1d62d524
work_keys_str_mv AT fionaemcalpine neuroinflammationandtumornecrosisfactorsignalinginthepathophysiologyofalzheimeramprsquosdisease
AT malampuacutegtansey neuroinflammationandtumornecrosisfactorsignalinginthepathophysiologyofalzheimeramprsquosdisease
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