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

Sang Ho Choi, Saba Aid, Luca Caracciolo, S. Sakura Minami, Takako Niikura, Yasuji Matsuoka, R. Scott Turner, Mark P. Mattson, Francesca Bosetti

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)59-68
Number of pages10
JournalJournal of Neurochemistry
Volume124
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

Fingerprint

Cyclooxygenase 1
Memory Disorders
Pathology
Amyloid
Alzheimer Disease
Data storage equipment
Amyloid Plaques
Microglia
Cyclooxygenase 2
Brain
Aptitude
Cyclooxygenase Inhibitors
Inhibition (Psychology)
Cyclooxygenase 2 Inhibitors
Deposits
Interleukins
Prostaglandin-Endoperoxide Synthases
Neuroglia
Brain Injuries
Cognition

Keywords

  • 3 × Tg-AD mice
  • Alzheimer's disease
  • COX-1
  • microglia
  • SC-560

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Choi, S. H., Aid, S., Caracciolo, L., Sakura Minami, S., Niikura, T., Matsuoka, Y., ... Bosetti, F. (2013). Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease. Journal of Neurochemistry, 124(1), 59-68. https://doi.org/10.1111/jnc.12059

Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease. / Choi, Sang Ho; Aid, Saba; Caracciolo, Luca; Sakura Minami, S.; Niikura, Takako; Matsuoka, Yasuji; Turner, R. Scott; Mattson, Mark P.; Bosetti, Francesca.

In: Journal of Neurochemistry, Vol. 124, No. 1, 01.2013, p. 59-68.

Research output: Contribution to journalArticle

Choi, SH, Aid, S, Caracciolo, L, Sakura Minami, S, Niikura, T, Matsuoka, Y, Turner, RS, Mattson, MP & Bosetti, F 2013, 'Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease', Journal of Neurochemistry, vol. 124, no. 1, pp. 59-68. https://doi.org/10.1111/jnc.12059
Choi, Sang Ho ; Aid, Saba ; Caracciolo, Luca ; Sakura Minami, S. ; Niikura, Takako ; Matsuoka, Yasuji ; Turner, R. Scott ; Mattson, Mark P. ; Bosetti, Francesca. / Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease. In: Journal of Neurochemistry. 2013 ; Vol. 124, No. 1. pp. 59-68.
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