NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. J Clin Invest

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 11/2009; 119(12):3692-702. DOI: 10.1172/JCI39716
Source: PubMed


Ectopic cell cycle events (CCEs) mark vulnerable neuronal populations in human Alzheimer disease (AD) and are observed early in disease progression. In transgenic mouse models of AD, CCEs are found before the onset of beta-amyloid peptide (Abeta) deposition to form senile plaques, a hallmark of AD. Here, we have demonstrated that alterations in brain microglia occur coincidently with the appearance of CCEs in the R1.40 transgenic mouse model of AD. Furthermore, promotion of inflammation with LPS at young ages in R1.40 mice induced the early appearance of neuronal CCEs, whereas treatment with 2 different nonsteroidal antiinflammatory drugs (NSAIDs) blocked neuronal CCEs and alterations in brain microglia without altering amyloid precursor protein (APP) processing and steady-state Abeta levels. In addition, NSAID treatment of older R1.40 animals prevented new neuronal CCEs, although it failed to reverse existing ones. Retrospective human epidemiological studies have identified long-term use of NSAIDs as protective against AD. Prospective clinical trials, however, have failed to demonstrate a similar benefit. Our use of CCEs as an outcome measure offers fresh insight into this discrepancy and provides important information for future clinical trials, as it suggests that NSAID use in human AD may need to be initiated as early as possible to prevent disease progression.

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Available from: Yan Yang, Feb 21, 2014
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    • "Furthermore, TREM2 overexpression in the brain of APPswe/PS1dE9 mice significantly attenuated neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive function. The neurotoxicity of Ab and proinflammatory cytokines led to the neuronal and synaptic damage in cellular and animal models of AD (Calkins and Reddy, 2011; Gouras et al, 2010; Kapadia and Sakic, 2011), which could be effectively prevented by Ab-targeting therapy or anti-inflammatory treatment (Adolfsson et al, 2012; Varvel et al, 2009). On consideration of this evidence, the attenuation of neuronal and synaptic losses by TREM2 overexpression was likely attributed to the amelioration of Ab neuropathology and neuroinflammation in this scenario. "
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    ABSTRACT: Triggering receptor expressed on myeloid cells 2 gene (TREM2) is a recently identified susceptibility gene for Alzheimer's disease (AD), since its low-frequency variants increase the risk of this disease with an odds ratio similar to that of one APOE ɛ4 allele. To date, the expression and biological functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was up-regulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this up-regulation was attributed to the increased amyloid-β (Aβ) 1-42 levels in brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aβ1-42 phagocytosis and inhibited Aβ1-42-triggered pro-inflammatory responses. Meanwhile, this modulation was depended on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aβ deposition, neuroinflammation and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the up-regulation of TREM2 serves as a compensatory response to Aβ1-42 and subsequently protects against AD progression via modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.Neuropsychopharmacology accepted article preview online, 22 July 2014; doi:10.1038/npp.2014.164.
    Full-text · Article · Jul 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "It is not unexpected that both the oxidative stress and inflammation could be attenuated by treatment with antioxidants, radical scavenger and/or non-steroidal anti-inflammatory drugs (NSAIDs) [7]. Experimental studies also show that NSAIDs are effective to reduce the amount of plaque formation in a mouse model of AD [8], whereas epidemiologic and clinical studies have shown inconsistent results. Omega-3 fatty acids (ω-3 FAs), e.g., eicosapentanoic acid (EPA; 20:5) and docosahexanoic acid (DHA; 22:6), present in fatty fish and fish oil, regulate inflammatory reactions and may possibly counteract the inflammation in neurodegenerative disorders with an inflammatory component including AD [9] [10] and delay cognitive decline in patients with very mild AD [11]. "
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    ABSTRACT: Background: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation. Objective: The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA. Methods: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F2-isoprostane, 8-iso-PGF2α, a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α, a major metabolite of PGF2α and biomarker of inflammatory response, were measured. Results: F2-isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2-isoprostanes and 15-keto-dihydro-PGF2α. At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid. Conclusion: The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.
    Full-text · Article · Jun 2014 · Journal of Alzheimer's disease: JAD
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    • "In spite of that it cannot be overlooked that not all results have been favorable, for example, in transgenic mice models of AD, COX-2 selective inhibitors failed to reduce the inflammatory reaction and showed an increase in the appearance of Aβ42 peptide (Kukar et al., 2005). Recent findings suggest that alterations in microglia and the production of cytokines and chemokines may be an early feature that precedes Aβ deposition in a mouse model of AD (Varvel et al., 2009). This early microglial activation may well play a role in the appearance of vulnerable neuronal populations, similarly to the situation in AD. "
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    ABSTRACT: Alzheimer disease (AD) is the most common cause of dementia in people over 60 years old. The molecular and cellular alterations that trigger this disease are still diffuse, one of the reasons for the delay in finding an effective treatment. In the search for new targets to search for novel therapeutic avenues, clinical studies in patients who used anti-inflammatory drugs indicating a lower incidence of AD have been of value to support the neuroinflammatory hypothesis of the neurodegenerative processes and the role of innate immunity in this disease. Neuroinflammation appears to occur as a consequence of a series of damage signals, including trauma, infection, oxidative agents, redox iron, oligomers of τ and β-amyloid, etc. In this context, our theory of Neuroimmunomodulation focus on the link between neuronal damage and brain inflammatory process, mediated by the progressive activation of astrocytes and microglial cells with the consequent overproduction of proinflammatory agents. Here, we discuss about the role of microglial and astrocytic cells, the principal agents in neuroinflammation process, in the development of neurodegenerative diseases such as AD. In this context, we also evaluated the potential relevance of natural anti-inflammatory components, which include curcumin and the novel Andean Compound, as agents for AD prevention and as a coadjuvant for AD treatments.
    Full-text · Article · Apr 2014 · Frontiers in Cellular Neuroscience
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