title: Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu.
abstract: Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ)-containing plaques within the brain that is accompanied by a robust microglial-mediated inflammatory response. This inflammatory response is reliant upon engagement of innate immune signaling pathways involving the toll-like receptors (TLRs). Studies assessing the roles of TLRs in AD pathogenesis have yielded conflicting results. We have assessed the roles of the TLRs through genetic inactivation of the TLR2/4 coreceptor, CD14, in a transgenic murine model of AD. Transgenic mice lacking CD14 exhibited reduced insoluble, but not soluble, levels of Aβ at 7 months of age. This corresponded with decreased plaque burden resulting from a reduction in number and size of both diffuse and thioflavin S-positive plaques and an overall reduction in the number of microglia. These findings are inconsistent with the established actions of these receptors. Moreover, loss of CD14 expression was associated with increased expression of genes encoding the proinflammatory cytokines Tnfα and Ifnγ, decreased levels of the microglial/macrophage alternative activation markers Fizz1 and Ym1, and increased expression of the anti-inflammatory gene Il-10. Thus, the loss of CD14 resulted in a significant change in the inflammatory environment of the brain, likely reflecting a more heterogeneous population of microglia within the brains of the animals. The reduction in plaque burden was not a result of changes in the expression of various Aβ degrading enzymes or proteins associated with Aβ clearance. These data suggest that CD14 is a critical regulator of the microglial inflammatory response that acts to modulate Aβ deposition.
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Erin G
authors.initials: EG
authors.lastname: Reed-Geaghan
authors.forename: Quillan W
authors.initials: QW
authors.lastname: Reed
authors.forename: Paige E
authors.initials: PE
authors.lastname: Cramer
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors