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

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.

• Authors: Sang-Ho Choi, Saba Aid, Luca Caracciolo, S Sakura Minami, Takako Niikura, Yasuji Matsuoka, R Scott Turner, Mark P Mattson, Francesca Bosetti
• Journal: Journal of neurochemistry (J Neurochem) Vol. 124 Issue 1 Pg. 59-68 (Jan 2013) ISSN: 1471-4159 [Electronic] England
• PMID: 23083210 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Published 2012. This article is a US Government work and is in the public domain in the USA.

Chemical References

• Amyloid beta-Protein Precursor
• Amyloidogenic Proteins
• Cyclooxygenase Inhibitors
• Glial Fibrillary Acidic Protein
• PSEN1 protein, human
• Presenilin-1
• Pyrazoles
• SC 560
• tau Proteins
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3

Topics

• Alzheimer Disease (complications, genetics, pathology)
• Amyloid beta-Protein Precursor (genetics)
• Amyloidogenic Proteins (metabolism)
• Animals
• Cyclooxygenase Inhibitors (therapeutic use)
• Disease Models, Animal
• Gene Expression Regulation (drug effects, genetics)
• Glial Fibrillary Acidic Protein (metabolism)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Male
• Maze Learning (drug effects)
• Memory Disorders (drug therapy, etiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (drug effects)
• Mutation (genetics)
• Phagocytes (drug effects)
• Phosphorylation (drug effects)
• Presenilin-1 (genetics)
• Pyrazoles (therapeutic use)
• tau Proteins (genetics)