Microglial EP2 as a new target to increase amyloid beta phagocytosis and decrease amyloid beta-induced damage to neurons.
Epidemiologic and animal model data support a role for the prostaglandin pathway in AD pathogenesis. However, unexpected toxicity from protracted use of some nonsteroidal anti-inflammatory drugs (NSAIDs) compels investigation of therapeutic targets in this pathway other than COX inhibitors. Previously, we have shown that mice lacking one specific receptor for PGE2, EP2 (EP2-/-), are protected from the indirect neurotoxic effects of cerebral innate immune response mediated by CD14-dependent activation. Here we review data showing that EP2-/- microglia have a highly desirable combination of features: ablated indirect neurotoxicity following exposure to Abeta(1-42) coupled with enhanced phagocytosis of Abeta peptides, both synthetic and those deposited in human brain. These data point to microglial EP2 as a more focused target within the PG pathway for therapy in AD.
Shie
Feng-Shiun
FS
Department of Pathology, University of Washington, Seattle 98104, USA.
Montine
Kathleen S
KS
Breyer
Richard M
RM
Montine
Thomas J
TJ
D000544:Alzheimer Disease / Q000473:pathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D001921:Brain / Q000473:pathology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010587:Phagocytosis; D018078:Receptors, Prostaglandin E / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018950:Lipopolysaccharide Receptors; D018078:Receptors, Prostaglandin E