Protective effects of NSAIDs on the development of Alzheimer disease

Boston University School of Medicine, Clinical Epidemiology Research and Training Unit, 650 Albany St., Suite X200, Boston, MA 02118, USA.
Neurology (Impact Factor: 8.29). 05/2008; 70(19):1672-7. DOI: 10.1212/01.wnl.0000311269.57716.63
Source: PubMed


Nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD), but observational studies and trials have offered contradictory results. Prior studies have also been relatively short and small. We examined the effects on AD risk of NSAID use for >5 years and of NSAIDs that suppress formation of A beta (1-42) amyloid in a large health care database.
Cases were veterans aged 55 years and older with incident AD using the US Veterans Affairs Health Care system. Matched controls were drawn from the same population. NSAID exposure was categorized into seven time periods: no use, <or=1 year, >1 but <or=2 years, and so on. Using conditional logistic regression, adjusted for race and comorbidities, we tested the association between AD development and the use of 1) any NSAID, 2) any NSAID excluding nonacetylated salicylates, 3) each NSAID class, 4) each individual NSAID, and 5) A beta (1-42)-suppressing NSAIDs.
We identified 49,349 cases and 196,850 controls. Compared with no NSAID use, the adjusted odds ratios for AD among NSAID users decreased from 0.98 for <or=1 year of use (95% CI 0.95-1.00) to 0.76 for >5 years of use (0.68-0.85). For users of ibuprofen, it decreased from 1.03 (1.00-1.06) to 0.56 (0.42-0.75). Effects of other NSAID classes and individual NSAIDs were inconsistent. There was no difference between a group of A beta (1-42)-suppressing NSAIDs and others. Discussion: Long-term nonsteroidal anti-inflammatory drug (NSAID) use was protective against Alzheimer disease. Findings were clearest for ibuprofen. A beta (1-42)-suppressing NSAIDs did not differ from others.

Download full-text


Available from: Steven C Vlad, Sep 28, 2015
  • Source
    • "We find that large SGs are characteristic of MG in the brains of patients with advanced AD, suggesting that these cells have been exposed to persistent stress stimuli. This is consistent with observations that oxidative stress often precedes the pathogenesis of AD since enhanced neuroinflammation resulting from traumatic brain injury or infection predispose individuals to AD (Perry et al., 2002; Griffin, 2013) while the long-term use of NSAIDS can be protective (Vlad et al., 2008). The pronounced sensitivity of primary MG from aged mice to SA-or Aβ-induced SGs suggests that MG in the brains of elderly patients may be particularly prone to the stress-induced formation of SGs consistent with advanced age as the Fig. 8 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Microglial cells in the brains of Alzheimer's patients are known to be recruited to amyloid-beta (Aβ) plaques where they exhibit an activated phenotype, but are defective for plaque removal by phagocytosis. In this study, we show that microglia stressed by exposure to sodium arsenite or Aβ(1–42) peptides or fibrils form extensive stress granules (SGs) to which the tyrosine kinase, SYK, is recruited. SYK enhances the formation of SGs, is active within the resulting SGs and stimulates the production of reactive oxygen and nitrogen species that are toxic to neuronal cells. This sequestration of SYK inhibits the ability of microglial cells to phagocytose Escherichia coli or Aβ fibrils. We find that aged microglial cells are more susceptible to the formation of SGs; and SGs containing SYK and phosphotyrosine are prevalent in the brains of patients with severe Alzheimer's disease. Phagocytic activity can be restored to stressed microglial cells by treatment with IgG, suggesting a mechanism to explain the therapeutic efficacy of intravenous IgG. These studies describe a mechanism by which stress, including exposure to Aβ, compromises the function of microglial cells in Alzheimer's disease and suggest approaches to restore activity to dysfunctional microglial cells.
    10/2015; DOI:10.1016/j.ebiom.2015.09.053
  • Source
    • "Although mechanisms that cause AD are poorly understood, recent studies support the role of inflammation in hippocampal degeneration in AD. First, long-term use of nonsteroidal anti-inflammatory drugs has been shown to be protective for AD [7]. Second , activated astrocytes and microglia are seen in close association with amyloid plaques in the human ISSN 1387-2877/15/$35.00 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer’s disease (AD) is the most common form of dementia. Despite intense investigations, no effective therapy is available to halt its progression. We found that NF-κ B was activated within the hippocampus and cortex of AD subjects and that activated forms of NF-κ B negatively correlated with cognitive function monitored by Mini-Mental State Examination and global cognitive z score. Accordingly, NF-κ B activation was also observed in the hippocampus of a transgenic (5XFAD) mouse model of AD. It has been shown that peptides corresponding to the NF-κ B essential modifier (NEMO)-binding domain (NBD) of Iκ B kinase α (IKKα ) or Iκ B kinase β (IKKβ) specifically inhibit the induction of NF-κ B activation without inhibiting the basal NF-κ B activity. Interestingly, after intranasal administration, wild-type NBD peptide entered into the hippocampus, reduced hippocampal activation of NF-κ B, suppressed hippocampal microglial activation, lowered the burden of Aβ in the hippocampus, attenuated apoptosis of hippocampal neurons, protected plasticity-related molecules, and improved memory and learning in 5XFAD mice. Mutated NBD peptide had no such protective effect, indicating the specificity of our finding. These results suggest that selective targeting of NF-κ B activation by intranasal administration of NBD peptide may be of therapeutic benefit for AD patients.
    Journal of Alzheimer's disease: JAD 09/2015; 47(2):385-402. DOI:10.3233/JAD-150040 · 4.15 Impact Factor
  • Source
    • "Aging has been associated with an increasing neuroinflammatory process (Richwine et al., 2005; Ye and Johnson, 1999), and systemic inflammation may be associated with several pathologies, such as, coronary heart disease, diabetes, multiple sclerosis, Alzheimer's disease, and Parkinson's disease (Fito et al., 2007). However, anti-inflammatory therapies have shown mixed and discouraging results (Imbimbo et al., 2010; In t' Veld et al., 2001; Stewart et al., 1997; Vlad et al., 2008). Dietary strategies visibly influence inflammation, as related through both observational studies and controlled feeding trials in which subjects had limited food consumption (Giugliano et al., 2006; Harvie et al., 2011; Johnson et al., 2007; Mozaffarian et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic neuroinflammation is a common characteristic of neurodegenerative diseases, and lipopolysaccharide (LPS) signaling is linked to glutamate-nitric oxide-Na,K-ATPase isoforms pathway in central nervous system (CNS) and also causes neuroinflammation. Intermittent fasting (IF) induces adaptive responses in the brain that can suppress inflammation, but the age-related effect of IF on LPS modulatory influence on nitric oxide-Na,K-ATPase isoforms is unknown. This work compared the effects of LPS on the activity of α1,α2,3 Na,K-ATPase, nitric oxide synthase gene expression and/or activity, cyclic guanosine monophosphate, 3-nitrotyrosine-containing proteins, and levels of thiobarbituric acid-reactive substances in CNS of young and older rats submitted to the IF protocol for 30 days. LPS induced an age-related effect in neuronal nitric oxide synthase activity, cyclic guanosine monophosphate, and levels of thiobarbituric acid-reactive substances in rat hippocampus that was linked to changes in α2,3-Na,K-ATPase activity, 3-nitrotyrosine proteins, and inducible nitric oxide synthase gene expression. IF induced adaptative cellular stress-response signaling pathways reverting LPS effects in rat hippocampus of young and older rats. The results suggest that IF in both ages would reduce the risk for deficits on brain function and neurodegenerative disorders linked to inflammatory response in the CNS. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of aging 02/2015; 36(5). DOI:10.1016/j.neurobiolaging.2015.02.020 · 5.01 Impact Factor
Show more