title: Prostaglandin E2 receptor subtype 2 regulation of scavenger receptor CD36 modulates microglial Aβ42 phagocytosis.
abstract: Recent studies underline the potential relevance of microglial innate immune activation in Alzheimer disease. Primary mouse microglia that lack prostaglandin E2 receptor subtype 2 (EP2) show decreased innate immune-mediated neurotoxicity and increased amyloid β (Aβ) peptide phagocytosis, features that were replicated in vivo. Here, we tested the hypothesis that scavenger receptor CD36 is an effector of EP2-regulated Aβ phagocytosis. CD36 expression was 143-fold greater in mouse primary microglia than in primary astrocytes. Three different means of suppressing EP2 signaling increased and an agonist of EP2 decreased CD36 expression in primary wild-type microglia. Activation of Toll-like receptor (TLR) 3, TLR4, and TLR7, but not TLR2 or TLR9, reduced primary microglial CD36 transcription and cell surface CD36 protein and reduced Aβ42 phagocytosis as well. At each step, the effects of innate immune activation on CD36 were reversed by at least 50% by an EP2 antagonist, and this partial rescue of microglia Aβ42 phagocytosis was largely mediated by CD36 activity. Finally, we showed in hippocampus of wild-type mice that innate immune activation suppressed CD36 expression by an EP2-dependent mechanism. Taken together with results of others that found brain clearance of Aβ peptides and behavioral improvements mediated by CD36 in mice, regulation of CD36-mediated Aβ phagocytosis by suppression of EP2 signaling may provide a new approach to suppressing some aspects of Alzheimer disease pathogenesis.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington. Electronic address: xli@uw.edu.
authors.forename: Xianwu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Erica
authors.initials: E
authors.lastname: Melief
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Nadia
authors.initials: N
authors.lastname: Postupna
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism*; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D007113:Immunity, Innate; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D009498:Neurotoxins / Q000737:chemistry; D010446:Peptide Fragments / Q000378:metabolism*; D010587:Phagocytosis; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018955:CD36 Antigens; D009498:Neurotoxins; D010446:Peptide Fragments; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051193:Toll-Like Receptors; C075222:amyloid beta-protein (1-42)