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Cyclooxygenase‐1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease
Author(s) -
Choi SangHo,
Aid Saba,
Caracciolo Luca,
Sakura Minami S.,
Niikura Takako,
Matsuoka Yasuji,
Turner R. Scott,
Mattson Mark P.,
Bosetti Francesca
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12059
Subject(s) - neuroinflammation , microglia , cyclooxygenase , neuropathology , hyperphosphorylation , alzheimer's disease , medicine , pharmacology , amyloid beta , neuroscience , inflammation , pathology , disease , psychology , biology , microbiology and biotechnology , biochemistry , kinase , enzyme
Several epidemiological and preclinical studies suggest that non‐steroidal anti‐inflammatory drugs ( NSAID s), 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 .