title: MyD88 deficiency ameliorates β-amyloidosis in an animal model of Alzheimer's disease.
abstract: The accumulation of β-amyloid protein (Aβ) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar Aβ plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful Aβ and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). Aβ aggregates can activate microglia by interacting with multiple toll-like receptors (TLRs), the pattern-recognition receptors of the innate immune system. Because the adapter protein MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88(-/-)) on Aβ accumulation and microglial activation in an AD mouse model. MyD88 deficiency decreased Aβ load and microglial activation in the brain. The decrease in Aβ load in an MyD88(-/-) AD mouse model was associated with increased and decreased protein expression of apolipoprotein E (apoE) and CX3CR1, respectively, compared with that in an MyD88 wild-type AD mouse model. These results suggest that MyD88 deficiency may reduce Aβ load by enhancing the phagocytic capability of microglia through fractalkine (the ligand of CX3CR1) signaling and by promoting apoE-mediated clearance of Aβ from the brain. These findings also suggest that chronic inflammatory responses induced by Aβ accumulation via the MyD88-dependent signaling pathway exacerbate β-amyloidosis in AD.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Lim
authors.forename: Jinghong
authors.initials: J
authors.lastname: Kou
authors.forename: Min
authors.initials: M
authors.lastname: Song
authors.forename: Abhinandan
authors.initials: A
authors.lastname: Pattanayak
authors.forename: Jingji
authors.initials: J
authors.lastname: Jin
authors.forename: Robert
authors.initials: R
authors.lastname: Lalonde
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Fukuchi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism*; D054022:Cerebrum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency*; D019707:Receptors, Chemokine / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D053594:Myeloid Differentiation Factor 88; D019707:Receptors, Chemokine