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

Authors

  • Sang-Ho Choi,

    1. Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
    Current affiliation:
    1. Cerebral Microcirculation Unit, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
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    • These authors contributed equally to this study.
  • Saba Aid,

    1. Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
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    • These authors contributed equally to this study.
  • Luca Caracciolo,

    1. Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
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  • S. Sakura Minami,

    1. Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA
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  • Takako Niikura,

    1. Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA
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  • Yasuji Matsuoka,

    1. Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA
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  • R. Scott Turner,

    1. Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA
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  • Mark P. Mattson,

    1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA
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  • Francesca Bosetti

    Corresponding authorCurrent affiliation:
    1. Division of Extramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
    • Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
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Address correspondence and reprint requests to Francesca Bosetti, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Blvd. Rm. 2115, Bethesda, MD 20892-9521, USA. E-mail: frances@mail.nih.gov

Abstract

Several epidemiological and preclinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β-amyloid (Aβ) production and inhibit neuroinflammation. However, follow-up clinical trials, mostly using selective cyclooxygenase (COX)-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX-1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro-inflammatory stimuli including Aβ, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX-1 inhibition, rather than COX-2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20-month-old triple transgenic AD (3 × Tg-AD) mice with the COX-1 selective inhibitor SC-560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC-560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg-AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX-1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg-AD mice. Thus, selective COX-1 inhibition should be further investigated as a potential therapeutic approach for AD.

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