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.

journal_name

J Neurochem

authors

Choi SH,Aid S,Caracciolo L,Minami SS,Niikura T,Matsuoka Y,Turner RS,Mattson MP,Bosetti F

doi

10.1111/jnc.12059

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

59-68

issue

1

eissn

0022-3042

issn

1471-4159

journal_volume

124

pub_type

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