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.
"This reduction of Aβ42 was accompanied by a concomitant increase in Aβ38, a shorter, less amyloidogenic Aβ peptide , rather than the inhibition of all carboxyl-terminal processing of APP [22,23]. Furthermore, they demonstrated that the effects of NSAIDs on the preferential reduction of Aβ42 peptide levels were not linked to the inhibition of COX or other enzymes, but rather to a specific action on γ-secretase [22,24]. The shift in production of Aβ peptides from the longer, toxic forms to the shorter, less toxic forms by NSAIDs has been termed γ-secretase modulation. "
[Show abstract][Hide abstract] ABSTRACT: Background
A hallmark of Alzheimer’s disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer’s disease.
Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM) and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits.
EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that γ-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer’s disease.
"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. "
[Show abstract][Hide abstract] 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 · 1.54 Impact Factor
"Additional mechanisms by which NSAIDs can affect microglial activation process include their ability of modulate the activity and/or expression of crucial signaling molecules. A subset of NSAIDs (sodium salicylate, ASA, flurbiprofen, and the selective COX-2 inhibitor rofecoxib), are able to target NF-κB [60,61,62], a transcription factor involved in the control of cell growth, survival, plasticity, memory formation, cognition and behavior, and modulation of β-secretase (BACE1) expression [63,64]. In microglia NF-κB is a key signaling molecule, which regulates the transcription of pro-inflammatory genes, immunoreceptors, metalloproteinases and cell adhesion molecules . "
[Show abstract][Hide abstract] ABSTRACT: The term NSAID refers to structurally diverse chemical compounds that share the ability to inhibit the activity of the prostaglandin (PG) biosynthetic enzymes, the cyclooxygenase (COX) isoforms 1 and 2. The suppression of PG synthesis at sites of inflammation has been regarded as primarily responsible for the beneficial properties of NSAIDs, but several COX-independent effects have been described in recent years. Epidemiological studies indicate that NSAIDs are neuroprotective, although the mechanisms underlying their beneficial effect remain largely unknown. Microglial cells play a major role in brain inflammation and are often viewed as major contributors to the neurodegeneration. Therefore, microglia represent a likely target for NSAIDs within the brain. In the present review, we focused on the direct effects of NSAIDs and selective COX-2 inhibitors on microglial functions and discuss the potential efficacy in controlling brain inflammation.
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