These authors contributed equally to this study.
Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease
Article first published online: 21 NOV 2012
Published 2012. This article is a US Government work and is in the public domain in the USA
Journal of Neurochemistry
Volume 124, Issue 1, pages 59–68, January 2013
How to Cite
J. Neurochem. (2013) 124, 59–68.
- Issue published online: 6 DEC 2012
- Article first published online: 21 NOV 2012
- Accepted manuscript online: 20 OCT 2012 05:39AM EST
- Manuscript Accepted: 10 OCT 2012
- Manuscript Revised: 28 SEP 2012
- Manuscript Received: 18 JUN 2012
- Intramural Research Program of the National Institute on Aging
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health
- National Institutes of Health. Grant Number: R01 AG026478
- 3 × Tg-AD mice;
- Alzheimer's disease;
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.