The Non-cyclooxygenase Targets of Non-steroidal Anti-inflammatory Drugs, Lipoxygenases, Peroxisome Proliferator-activated Receptor, Inhibitor of κB Kinase, and NFκB, Do Not Reduce Amyloid β42 Production
ABSTRACT Epidemiological evidence suggests that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of Alzheimer's disease. Recently, NSAIDs have been shown to decrease amyloid pathology in a transgenic mouse model of Alzheimer's disease. This benefit may be partially attributable to the ability of NSAIDs to selectively reduce production of the amyloidogenic A beta 42 peptide in both cultured cells and transgenic mice. Although this activity does not appear to require the action of cyclooxygenases in cultured cells, it is not known whether other NSAID-sensitive targets contribute to this A beta 42 effect. In this study, we have used both pharmacological and genetic means to determine if other known cellular targets of NSAIDs could mediate the reduction in A beta 42 secretion from cultured cells. We find that altered arachidonic acid metabolism via NSAID action on cyclooxygenases and lipoxygenases does not alter A beta 42 production. Furthermore, we demonstrate that alterations in activity of peroxisome proliferator-activated receptors, I kappa B kinase beta or nuclear factor kappa B do not affect A beta 42 production. Thus, NSAIDs do not appear to alter A beta 42 production indirectly through previously identified cellular targets and may interact directly with the gamma-secretase complex itself to affect amyloid production.
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- "Some modulators exhibit non-linear or non-competitive kinetics, and may act at structural modification or at allosteric sites of c-SC, including sulfonamides, benzodiazopenes , Liþ, casein kinase inhibitors, or kinase inhibitors (Tian et al., 2002; Churcher et al., 2003; Owens et al., 2003; Phiel et al., 2003; Flajolet et al., 2007). Long-term administration of non-steroid anti-inflammatory drugs, showing beneficial effects, was believed to target allosteric sites of c-SC or nucleotide binding sites within c-SC, reducing amyloidogenesis while sparing the Notch signaling pathway (Eriksen et al., 2003; Sagi et al., 2003; Zhou et al., 2003; Fraering et al., 2005). At least two promising c-SC inhibitors have been clinically tested. "
ABSTRACT: One of the main neuropathological lesions observed in brain autopsy of Alzheimer's disease (AD) patients is the extracellular senile plaques mainly composed of amyloid-beta (Aβ) peptide. Recently, treatment strategies have focused on modifying the formation, clearance, and accumulation of this potentially neurotoxic peptide. β- and γ-secretase are responsible for the cleavage of amyloid precursor protein (APP) and the generation of Aβ peptide. Treatments targeting these two critical secretases may therefore reduce Aβ peptide levels and positive impact on AD. Vaccination is also an advanced approach against Aβ. This review focuses on recent advances of our understanding of this key peptide, with emphasis on Aβ peptide synthesis, accumulation and neurotoxicity, and current therapies including vaccination and two critical secretase inhibitors. MicroRNAs (miRNAs) are a class of conserved endogenous small noncoding RNAs, known to regulate the expression of complementary messenger RNAs, involved in AD development. We therefore address the relationship of miRNAs in the brain and Aβ generation, as a novel therapeutic approach to the treatment of AD while also providing new insights on the etiology of this neurological disorder.The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 08/2011; 294(8):1307-18. DOI:10.1002/ar.21425 · 1.53 Impact Factor
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- "The effectiveness of flurbiprofen, ibuprofen and sulindac sulfide for lowering A production has been confirmed using primary neurons as the target cell , but this study did not report the specific effect to A(42) as these agents were effective at lowering A(40) production as well. These authors concluded that the mechanism of action of these NSAIDs is not related to their COX, lipoxygenase, NFB or IB inhibiting-, or PPAR-activating-, properties, as specific agents for these targets did not affect A levels in the assays used . The effect appeared to be due to inhibition of Rho and a Rho-kinase . "
ABSTRACT: From the initial characterizations of inflammatory responses in Alzheimer’s disease (AD) affected brains, namely the demonstration of activated microglia and reactive astrocytes, complement system activation, increased production of proinflammatory cytokines, and evidence for microglial-produced neurotoxins, there was hope that reducing inflammation might be a feasible treatment for this memory-robbing disease. This hope was supported by a number of epidemiology studies demonstrating that patients who took non-steroidal anti-inflammatory drugs had significantly lower risk of developing AD. However, clinical trials of anti-inflammatories have not shown effectiveness, and in recent years, the concept of immune therapy has become a treatment option as animal studies and clinical trials with Aβ vaccines have demonstrated enhanced amyloid removal through stimulation of microglial phagocytosis. This review will examine the current status of whether inhibiting inflammation is a valid therapeutic target for treating AD; what lessons have come from the clinical trials; what new pathways and classes of agents are being considered; and how this field of research can progress towards new therapeutics. We will examine a number of agents that have shown effectiveness in reducing inflammation amongst other demonstrated mechanisms of action. The major focus of much AD drug discovery has been in identifying agents that have anti-amyloid properties; however, a number of these agents were first identified for their anti-inflammatory properties. As drug development and clinical testing is a costly and lengthy endeavor, sound justification of new therapeutic targets is required. Possible future directions for AD anti-inflammatory or immune clearance therapy will be discussed based on recent experimental data.Current Neuropharmacology 01/2008; 5(4):232-43. DOI:10.2174/157015907782793667 · 2.35 Impact Factor
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- "Because epidemiological studies indicate that long-term intake of non-steroidal anti-inflammatory drugs reduces the risk of developing AD (in't Veld et al., 2001), one of the proposed approaches for AD therapy considers the use of molecules inhibiting neuroinflammatory phenomena. Indeed, a subset of non-steroidal anti-inflammatory drugs also affects amyloid production, by reducing the secretion of Ab42 from cultured cells, independently of their effects on cyclooxygenase activity (Weggen et al., 2001; Sagi et al., 2003). Their direct interaction with the c-secretase complex in cell-free assays (Takahashi et al., 2003; Weggen et al., 2003) has further suggested that they may act by preventing neurodegeneration besides contrasting inflammatory response. "
ABSTRACT: Beta-amyloid (Abeta) peptides are key proteins in the pathophysiology of Alzheimer's disease (AD). While Abeta42 aggregates very rapidly to form early diffuse plaques, supplemental Abeta40 deposition is required to form mature neuritic plaques. We here investigated the role of nuclear factor-kappaB (NF-kappaB) pathway in Abeta40-mediated neuronal damage and amyloid pathology. In rat primary neurons and human postmitotic neuronal cells, the Abeta peptide induced a dose-dependent neuronal death, reduced the levels of the anti-apoptotic protein Bcl-XL, enhanced the cytosolic release of cytochrome c, and elicited the intracellular accumulation and secretion of Abeta42 oligomers. Moreover, Abeta40 activated the NF-kappaB pathway by selectively inducing the nuclear translocation of p65 and p50 subunits, and promoted an apoptotic profile of gene expression. As inhibitors of the NF-kappaB pathway, we tested the capability of a double-stranded kappaB decoy oligonucleotide, the anti-inflammatory drug aspirin and the selective IkappaB kinase 2 inhibitor, AS602868, to modify the Abeta40-mediated effects. These treatments, transiently applied before Abeta exposure, completely inhibited p50/p65 nuclear translocation and neuronal damage. The kappaB decoy also inhibited the Abeta-induced release of cytochrome c, restored the levels of Bcl-XL, and prevented intraneuronal accumulation and secretion of Abeta42. These results open up interesting perspectives on the development of novel strategies targeting out NF-kappaB p50/p65 dimers for pharmacological intervention in AD.European Journal of Neuroscience 05/2006; 23(7):1711-20. DOI:10.1111/j.1460-9568.2006.04722.x · 3.67 Impact Factor