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. The role of COX-1 in AD has not been considered carefully in part due to the presumed predominant role of COX-2 in neuroinflammation. Here we show that the COX-1 inhibitor SC-560 reduces amyloid deposits and improves memory deficits in 3 × Tg-AD mice. These results suggest that COX-1 should be further considered as a potential target for therapeutic intervention.
Original language | English (US) |
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Pages (from-to) | 59-68 |
Number of pages | 10 |
Journal | Journal of Neurochemistry |
Volume | 124 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2013 |
Externally published | Yes |
Keywords
- 3 × Tg-AD mice
- Alzheimer's disease
- COX-1
- microglia
- SC-560
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience