Cyclooxygenase‐1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease

Choi, Sang Ho; Aïd, Saba; Caracciolo, Luca; Minami, S. Sakura; Niikura, Takako; Matsuoka, Yasuji; Turner, R. Scott; Mattson, Mark P.; Bosetti, Francesca

doi:10.1111/jnc.12059

Cited by 104 publications

(76 citation statements)

References 56 publications

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“…Moreover, the COX-1-selective inhibitor SC-560 reduces amyloid deposits and tau hyperphosphorylation and improves spatial learning and memory in triple transgenic AD mice (25). In our study of APP-Tg mice, (S)-11 C-KTP-Me demonstrated age-dependent changes that closely corresponded to the increase in amyloid plaques as revealed by immunohistochemistry with an Ab 1-16 antibody.…”

Section: Discussionmentioning

confidence: 57%

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

Shukuri

Mawatari²,

Ohno³

et al. 2015

J Nucl Med

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Cyclooxygenase (COX), a prostanoid-synthesizing enzyme, is considered to be involved in the neuroinflammatory process of neurodegenerative diseases. However, the role of COX in the progression of neurodegeneration is not well understood. We hypothesized that in vivo imaging of COX by PET will contribute to elucidation of the function of COX during the neurodegenerative process in Alzheimer's disease (AD). 11 C-labeled ketoprofen methyl ester (racemic (RS)-11 C-KTP-Me) developed recently by our group is a useful PET probe for in vivo imaging of COX-1 during neuroinflammation. The (S)-enantiomer of ketoprofen is known to be pharmacologically more active than the (R)-enantiomer. We thus synthesized 11 C-labeled (S)-ketoprofen methyl ester ((S)-11 C-KTP-Me) as an improved PET probe specific for COX-1 and applied it for investigation of the changes in COX-1 during the progression of AD in a mouse model. Methods: The specificity of (S)-11 C-KTP-Me for COXs was examined in PET studies with rats that had intrastriatal injection of lipopolysaccharide. To determine the details of changes in COX-1 during progression of amyloid-β (Aβ) plaque formation in amyloid precursor protein transgenic (APP-Tg) mice, we performed immunohistochemical studies and ex vivo autoradiography with (S)-11 C-KTP-Me. Results: PET studies using hemispheric lipopolysaccharide injection into rats revealed that the sensitivity of (S)-11 C-KTP-Me in neuroinflammation was much higher than that of (RS)-11 C-KTP-Me and (R)-11 C-KTP-Me; these results closely corresponded to the inhibitory activities of each enantiomer against COX-1 estimated by an in vitro assay. In APP-Tg mice, (S)-11 C-KTP-Me administration resulted in progressive and significant increases in accumulation of radioactivity in the brain from 16 to 24 mo old in accordance with the histopathologic appearance of abundant Aβ plaques and activated microglia, whereas few changes in radioactivity accumulation and few Aβ plaques were seen in age-matched wild-type control mice. High-radioactivity accumulation by (S)-11 C-KTP-Me was markedly observed in the frontal cortex and hippocampus in which COX-1-expressing activated microglia tightly surrounded and enclosed large and more intensely stained Aβ plaques, indicating neuroinflammation that originated with Aβ. Conclusion: (S)-11 C-KTP-Me is a potent PET probe that is highly selective for COX-1. Studies using APP-Tg mice demonstrated that (S)-11 C-KTP-Me could detect activated microglia that are associated with amyloid plaque progression, suggesting the involvement of COX-1 in the neuroinflammatory process in AD.

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Section: Discussionmentioning

confidence: 57%

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

Shukuri

Mawatari²,

Ohno³

et al. 2015

J Nucl Med

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“…In addition, some NSAIDs act as PPARγ agonists, inhibiting interleukin-6 (IL6) and RNF-alpha in microglia and monocytes (Combs et al, 1999) and preventing microglial activation (Combs et al, 2000). 3xTg-AD mice treated with a COX-1 selective inhibitor showed reduced glial activation and increased brain expression of anti-inflammatory markers along with learning and memory improvements and reduced Aβ deposits (Choi et al, 2013). Unfortunately, clinical trials have failed to show beneficial effects of NSAIDs in AD patients (Heneka et al, 2015).…”

Section: The Endocytic Pathway In Phagocytic Cellsmentioning

confidence: 99%

The endocytic pathway in microglia during health, aging and Alzheimer’s disease

Solé-Domènech

Cruz

Capetillo-Zárate

et al. 2016

Ageing Research Reviews

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Microglia, the main phagocytes of the central nervous system (CNS), are involved in the surveillance and maintenance of nervous tissue. During normal tissue homeostasis, microglia migrate within the CNS, phagocytose dead cells and tissue debris, and modulate synapse pruning and spine formation via controlled phagocytosis. In the event of an invasion by a foreign body, microglia are able to phagocytose the invading pathogen and process it proteolytically for antigen presentation. Internalized substrates are incorporated and sorted within the endocytic pathway and thereafter transported via complex vesicular routes. When targeted for degradation, substrates are delivered to acidic late endosomes and lysosomes. In these, the enzymatic degradation relies on pH and enzyme content. Endocytosis, sorting, transport, compartment acidification and degradation are regulated by complex signaling mechanisms, and these may be altered during aging and pathology. In this review, we discuss the endocytic pathway in microglia, with insight into the mechanisms controlling lysosomal biogenesis and pH regulation. We also discuss microglial lysosome function associated with Alzheimer’s disease (AD) and the mechanisms of amyloid-beta (Aβ) internalization and degradation. Finally, we explore some therapies currently being investigated to treat AD and their effects on microglial response to Aβ, with insight in those involving enhancement of lysosomal function.

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“…COX-mediated neuronal injury may be due to downstream effects of one or more prostaglandins (PGs) including PGE2, PGD2, PGF2␣, PGI2 (prostacylin), and TXA2 (thromboxane) that effect cellular changes through activation of specific PG receptor subtypes and second messenger system. Inhibition of COX activity with non-steroidal anti-inflammatory drugs reduces inflammation and A␤ accumulation in a mouse model of AD [183]. The other product of PLA 2 action, lysophospholipids, is not only converted into proinflammatory platelet activating factor but acts as a detergent at the cell membrane, leading to disturbance in ion homeostasis [184].…”

Section: Possible Links Between Ad Associated Lipid Changes and Slow mentioning

confidence: 99%

Slow Excitotoxicity in Alzheimer's Disease

Ong

Tanaka

Dawe

et al. 2013

JAD

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Abstract. Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as A␤PP/A␤ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD.

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Cyclooxygenase‐1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease

Cited by 104 publications

References 56 publications

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

The endocytic pathway in microglia during health, aging and Alzheimer’s disease

Slow Excitotoxicity in Alzheimer's Disease

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