Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease

Ba, in t' Veld; Ruitenberg, Annemieke; Hofman, Albert; Lj, Launer; Duijn, van; Stijnen, Theo; Breteler, Monique M.B.; Bh, Stricker

doi:10.1056/nejmoa010178

Cited by 1,067 publications

(500 citation statements)

References 42 publications

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“…The effects of EP2 receptor deletion may also be relevant to the preventive effects of chronic NSAID use against the development of AD (McGeer et al, 1996;Stewart et al, 1997;in t' Veld et al, 2001), in which decreased COX activity might lead to lower levels of downstream PGE 2 production and EP2 receptor signaling. However, it is important to note that several non-COXrelated effects of NSAIDs have been demonstrated, including effects of NSAIDs on transcription factors important in the inflammatory response, such as NF-B (nuclear factor B) and AP-1 (for review, see Tegeder et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Of relevance to early events in AD is the overwhelming evidence for a central role of inflammation and oxidative stress (Akiyama et al, 2000). Epidemiological data support a preventive as opposed to a therapeutic effect of COX inhibition in AD, in which nonsteroidal anti-inflammatory drug (NSAID) administration delays the onset and risk of developing AD (Breitner et al, 1995;McGeer et al, 1996;Stewart et al, 1997;in t' Veld et al, 2001;Szekely et al, 2004). This preventive effect has been modeled in transgenic mice expressing mutant forms of amyloid precursor protein (APP) and presenilin 1 (PS1), and, in these models, NSAIDs significantly reduce amyloid deposition (Lim et al, 2000;Jantzen et al, 2002; and microglial activation (Lim et al, 2000;.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Liang¹,

Wang²,

Hand³

et al. 2005

J. Neurosci.

219

202

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Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E 2 (PGE 2 ) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE 2 EP2 receptor in the APPSwe-PS1⌬E9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-␤ (A␤) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1⌬E9 mice lacking the EP2 receptor harbor lower levels of ␤ C-terminal fragments, the product of ␤-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE 2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased A␤ peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Liang¹,

Wang²,

Hand³

et al. 2005

J. Neurosci.

219

202

View full text Add to dashboard Cite

show abstract

“…[85][86][87][88] Some also argue that NSAIDs have no effect in patients already suspected to have developed AD 89 and that treatment with a COX-2 inhibitor increases the amount of b-amyloid found in the brain. 90 One must note that inhibition of COX-2 in the CNS has proinflammatory properties.…”

Section: Innate Immunity and Alzheimer's Diseasementioning

confidence: 99%

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

2006

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The role of innate immunity and microglia in the brain is currently a matter of great debate and controversy. While several studies have provided evidence that they contribute to neurodegeneration in various animal models of brain diseases and traumas, others have shown that their inhibition may in contrast be associated with more damages or less repair. We have recently reported the existence of two different types of microglia, the resident and the newly differentiated microglia that derive from the bone marrow stem cells. Of great interest is the fact that blood-derived microglial cells are associated with amyloid plaques and these cells are able to prevent the formation or eliminate the presence of amyloid deposits in mice that develop the major hallmark of Alzheimer's disease (AD). These newly recruited cells are specifically attracted to the b-amyloid 40/42 isoforms in vivo and they participate in the elimination of these proteins by phagocytosis. This review presents the mechanisms involved in the control of the innate immune response by microglia and the beneficial properties of such a response in brain diseases, such as AD.

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“…Both oxidative damage [4,24,28] and inflammation [3] begin early in AD accompanying amyloid accumulation and neurodegeneration. AD risk is reduced by anti-oxidant [20,34] and non-steroidal anti-inflammatory drug (NSAID) [11] intake suggesting these might be useful prevention methods.…”

Section: Introductionmentioning

confidence: 99%

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Cole

Lim

Yang

et al. 2005

Neurobiology of Aging

200

123

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Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.)

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Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease

Abstract: The long-term use of NSAIDs may protect against Alzheimer's disease but not against vascular dementia.

Cited by 1,067 publications

References 42 publications

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

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Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease

Abstract: The long-term use of NSAIDs may protect against Alzheimer's disease but not against vascular dementia.

Cited by 1,067 publications

References 42 publications

Deletion of the Prostaglandin E2EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Deletion of the Prostaglandin E2EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Contact Info

Product

Resources

About

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease