Inflammation and Alzheimer's disease

Akiyama, Haruhiko

doi:10.1016/s0197-4580(00)00124-x

Cited by 3,967 publications

(2,795 citation statements)

References 600 publications

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“…A chronic inflammatory response characterized by activated microglia, reactive astrocytes, complement factors, and increased inflammatory cytokine expression associated with Aß deposits has been described in the brain of AD patients (Rogers et al, 1996). A number of epidemiological studies have demonstrated a reduced risk for AD in population with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) in t'Veld et al, 1998;Akiyama et al, 2000;in t'Veld et al, 2001). These epidemiological findings have been supported by experimental studies.…”

Section: Introductionmentioning

confidence: 99%

“…Recent epidemiological studies have revealed that long-term and/or short-term use of some NSAIDs may protect against AD in t'Veld et al, 1998;Akiyama et al, 2000;in t'Veld et al, 2001). Our study and several reports on the effects of NSAIDs may well explain this correlation.…”

mentioning

confidence: 99%

“…Our study and several reports on the effects of NSAIDs may well explain this correlation. First, the major therapeutic effect of NSAIDs is believed to be due to their inhibition of COX-1 and COX-2, leading to the suppression of prostaglandin synthesis and chronic neuroinflammation contributing to the protracted degenerative course of AD (McGeer and McGeer, 1995;Akiyama et al, 2000). Second, Weggen et al (2001) recently suggested that a subset of NSAIDs including Ibu, SSide, Ind and R-Flu directly affect amyloid pathology in the brains of transgenic mouse by reducing the amount of soluble Aß(1-42) peptide levels independently of COX activity.…”

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confidence: 99%

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Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

et al. 2005

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The pathogenesis of Alzheimer's disease (AD) is characterized by cerebral deposits of amyloid ß-peptides (Aß) and neurofibrillary tangles which are surrounded by inflammatory cells. Long-term uses of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of developing AD and delay the onset of the disease. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of NSAIDs such as ibuprofen, aspirin, meclofenamic acid sodium salt, diclofenac sodium salt, ketoprofen, flurbiprofen, naproxen, sulindac sulfide and indomethacin on the formation, extension, and destabilization of ß-amyloid fibrils (fAß) at pH 7.5 at 37˚C in vitro. All examined NSAIDs dose-dependently inhibited formation of fAß from fresh Aß(1-40) and Aß(1-42), as well as their extension. Moreover, these NSAIDs dose-dependently destabilized preformed fAßs. The overall activity of the molecules examined was in the following order: ibuprofen ≈ sulindac sulfide ≥ meclofenamic acid sodium salt > aspirin ≈ ketoprofen ≥ flurbiprofen ≈ diclofenac sodium salt > naproxen ≈ indomethacin. Although the mechanisms by which these NSAIDs inhibit fAß formation from Aß, and destabilize preformed fAß in vitro are still unclear, NSAIDs may be promising for the prevention and treatment of AD.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

et al. 2005

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“…Key among these attempts are efforts to modulate the neuroinflammation that is a characteristic feature of both acute and chronic CNS disorders [1,18,22]. Neuroinflammation is a process that results primarily from an abnormally high or chronic activation of glia (microglia and astrocytes).…”

Section: Introductionmentioning

confidence: 99%

“…Neuronal damage/death can also induce glial activation, facilitating the propagation of a localized, detrimental cycle of neuroinflammation [8]. Accumulating evidence [1,6,9,13] suggests that targeting this glia-neuron cycle might be a therapeutic approach to Alzheimer's disease (AD) progression. However, progress in the pursuit of neuroinflammation as a therapeu-tic target in AD requires proof of concept that selective suppressors of glial activation can selectively modulate neuropathogenic aspects of the neuroinflammatory cycle, without impeding beneficial glial responses, in a robust animal model of AD-relevant neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Craft

Watterson

Frautschy

et al. 2004

Neurobiology of Aging

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The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer's disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (A␤)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human A␤1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1␤, tumor necrosis factor-␣ and S100B in the hippocampus. Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus, and diminished amyloid plaque deposition. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress A␤-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.

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Polymorphisms in Inflammatory Genes and the Risk of Alzheimer Disease

McGeer

McGeer²

2001

Arch Neurol

179

108

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The concept of inflammation as a major factor in Alzheimer disease (AD) has heretofore been based on postmortem findings of autodestructive changes associated with the lesions coupled with epidemiological evidence of a protective effect of anti-inflammatory agents. Now there is evidence that the risk of AD is substantially influenced by a total of 10 polymorphisms in the inflammatory agents interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, alpha(2)-macroglobulin, and alpha(1)-antichymotrypsin. The polymorphisms are all common ones in the general population, so there is a strong likelihood that any given individual will inherit 1 or more of the high-risk alleles. The overall chances of an individual developing AD might be profoundly affected by a "susceptibility profile" reflecting the combined influence of inheriting multiple high-risk alleles. Since some of the polymorphisms in question have already been linked to peripheral inflammatory disorders, such as juvenile rheumatoid arthritis, myasthenia gravis, and periodontitis, associations between AD and several chronic degenerative diseases may eventually be demonstrated. Such information could lead to strategies for therapeutic intervention in the early stages of such disorders.

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Inflammation and Alzheimer's disease

Cited by 3,967 publications

References 600 publications

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Polymorphisms in Inflammatory Genes and the Risk of Alzheimer Disease

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