title: Therapeutic implications of the prostaglandin pathway in Alzheimer's disease.
abstract: An important pathologic hallmark of Alzheimer's disease (AD) is neuroinflammation, a process characterized in AD by disproportionate activation of cells (microglia and astrocytes, primarily) of the non-specific innate immune system within the CNS. While inflammation itself is not intrinsically detrimental, a delicate balance of pro- and anti-inflammatory signals must be maintained to ensure that long-term exaggerated responses do not damage the brain over time. Non-steroidal anti-inflammatory drugs (NSAIDs) represent a broad class of powerful therapeutics that temper inflammation by inhibiting cyclooxygenase-mediated signaling pathways including prostaglandins, which are the principal mediators of CNS neuroinflammation. While historically used to treat discrete or systemic inflammatory conditions, epidemiologic evidence suggests that protracted NSAID use may delay AD onset, as well as decrease disease severity and rate of progression. Unfortunately, clinical trials with NSAIDs have thus far yielded disappointing results, including premature discontinuation of a large-scale prevention trial due to unexpected cardiovascular side effects. Here we review the literature and make the argument that more targeted exploitation of downstream prostaglandin signaling pathways may offer significant therapeutic benefits for AD while minimizing adverse side effects. Directed strategies such as these may ultimately help to delay the deleterious consequences of brain aging and might someday lead to new therapies for AD and other chronic neurodegenerative diseases.
authors.affiliation: University of Washington Harborview Medical Center, Department of Pathology, Box 359791, 325 Ninth Ave, Seattle, WA 98104, USA.
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.affiliation: University of Washington Harborview Medical Center, Department of Pathology, Box 359791, 325 Ninth Ave, Seattle, WA 98104, USA.
authors.forename: Nikolas L
authors.initials: NL
authors.lastname: Jorstad
authors.affiliation: University of Washington Harborview Medical Center, Department of Pathology, Box 359791, 325 Ninth Ave, Seattle, WA 98104, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: University of Washington Harborview Medical Center, Department of Pathology, Box 359791, 325 Ninth Ave, Seattle, WA 98104, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: University of Washington Harborview Medical Center, Department of Pathology, Box 359791, 325 Ninth Ave, Seattle, WA 98104, USA. Electronic address: cdkeene@uw.edu.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D011451:Prostaglandin-Endoperoxide Synthases
keywords: Alzheimer's disease; Cyclooxygenase; NSAID; Neuroinflammation; Prostaglandin