Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid

Abstract

Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletion on the inflammatory response and neurodegeneration induced by beta-amyloid. beta-amyloid (Abeta(1-42)) was centrally injected in the lateral ventricle of COX-1-deficient (COX-1(-/-)) and their respective wild-type (WT) mice. In COX-1(-/-) mice, Abeta(1-42)-induced inflammatory response and neuronal damage were attenuated compared to WT mice, as shown by Fluoro-Jade B and nitrotyrosine staining. These results indicate that inhibition of COX-1 activity may be valid therapeutic strategy to reduce brain inflammatory response and neurodegeneration.

Keywords: cyclooxygenase; microglia; neuroinflammation; neurotoxicity; oxidative stress.

Figure 1.. Increased microglial activation in the hippocampus 7 d after Aβ _1-42 administration.

Representative photomicrographs of the CA1 and CA3 of the hippocampus from WT mice (A, D) injected with Aβ_1-42 that shows numerous activated microglia with short, less-ramified processes, perikaryal hypertrophy, and amoeboid appearance (G). CA1 and CA3 areas of the hippocampus from Aβ_1-42-injected COX-1^-/- mice (B, E) show many resting microglia with ramified morphology (H). Scale bar: A-F, 100 μm; G-I, 50 μm. (J) Comparison of the number of activated microglia from the CA3 area. Mean ± SEM (n = 3-4 per group); ^**P < 0.01 compared with the Aβ_42-1-injected WT mice; ^##P < 0.01 compared with the Aβ_1-42-injected WT mice.

Figure 2.. Increased astrocytic activation in the hippocampus 7 d after Aβ _1-42 administration.

Representative photomicrographs of the CA1 and CA3 of the hippocampus from WT mice (A, D, G) injected with Aβ_1-42 that shows numerous robustly GFAP-immunoreactive astrocytes compared with Aβ_1-42-injected COX-1^-/- mice (B, E, H). Scale bar: A-F, 100 μm; G-I, 50 μm.

Figure 3.. Increased degenerating neurons in the hippocampus 7 d after.

Aβ_1-42 administration. (A-C) Representative photomicrographs of the CA3 of the hippocampus from WT mice (A) injected with Aβ_1-42 that shows numerous FJB-positive cells compared with Aβ_1-42-injected COX-1^-/- mice (B). Representative photomicro-graphs of DAPI (D-F) and Nissl staining (G-I) in the CA3 of hippocampus from Aβ_1-42-injected WT (D, G) and COX-1^-/-mice (E, H). Scale bar: A-I, 100 μm. (J) Comparison of the number of FJB-positive cells from the CA3 area. Mean ± SEM (n = 3-4 per group); ^**P < 0.01 compared with the Aβ_42-1-injected WT mice; ^##P < 0.01 compared with the Aβ_1-42-injected WT mice.

Figure 4.. Increased oxidative damage in the hippocampus 7 d after Aβ _1-42 administration.

Representative photomicrographs of the CA1 and CA3 of the hippocampus from WT mice (A, D) injected with Aβ_1-42 that show numerous robustly nitrotyrosine-immunoreactive cells compared with Aβ_1-42-injected COX-1^-/- mice (B, E). Scale bar: A-C, 100 μm; D-F, 50 μm.

Figure 5.. Effects of COX-1 deficiency on PG production 24 h after Aβ _1-42 administration.

Aβ_1-42-injected WT mice show significantly more PGE₂ (A), PGF_2α (B), and TXB₂ levels (C) than COX-1^-/- mice. Mean ± SEM (n = 3-4 per group); ^*P < 0.05, ^**P < 0.01 compared with the Aβ_42-1-injected WT mice; ^#P < 0.05, ^##P < 0.01 compared with the Aβ_1-42-injected WT mice.