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The Journal of Neuroscience, November 2, 2005, 25(44):10180-10187; doi:10.1523/JNEUROSCI.3591-05.2005
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Neurobiology of Disease
Deletion of the Prostaglandin E2 EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease
Xibin Liang,1
Qian Wang,1
Tracey Hand,1
Liejun Wu,1
Richard M. Breyer,3
Thomas J. Montine,4 and
Katrin Andreasson1,2
Departments of 1Neurology and 2Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 3Department of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and 4Department of Pathology, University of Washington, Seattle, Washington 98104
Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E2 (PGE2) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE2 EP2 receptor in the APPSwe-PS1 E9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid- (A) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1E9 mice lacking the EP2 receptor harbor lower levels of C-terminal fragments, the product of -site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased A peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.
Key words: prostaglandin; receptor; transgenic; inflammation; A peptide; Alzheimer's disease
Received Aug 24, 2005;
revised September 20, 2005;
accepted September 23, 2005.
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|
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|
|
|
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|
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