title: TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease.
abstract: BACKGROUND
  Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Aβ deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Aβ deposits and buffer-soluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of Aβ deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when Aβ deposits start.
  
  
  METHODS
  Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble Aβ were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and Aβ-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze.
  
  
  RESULTS
  While no difference was found in cerebral Aβ load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg) was less than that in a TLR4 wild-type AD model (TLR4W Tg). At 9 months, TLR4M Tg mice had increased Aβ deposition and soluble Aβ42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1β, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished Aβ-induced IL-1β, CCL3, and CCL4 expression in monocytes.
  
  
  CONCLUSIONS
  This is the first demonstration of TLR4-dependent activation of microglia at the early stage of β-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of Aβ deposition and that, as Aβ deposits start, microglia are activated via TLR4 signaling to reduce Aβ deposits and preserve cognitive functions from Aβ-mediated neurotoxicity.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, PO Box 1649, Peoria, IL 61656, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Song
authors.forename: Jingji
authors.initials: J
authors.lastname: Jin
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Lim
authors.forename: Jinghong
authors.initials: J
authors.lastname: Kou
authors.forename: Abhinandan
authors.initials: A
authors.lastname: Pattanayak
authors.forename: Jamaal A
authors.initials: JA
authors.lastname: Rehman
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Kim
authors.forename: Kazuki
authors.initials: K
authors.lastname: Tahara
authors.forename: Robert
authors.initials: R
authors.lastname: Lalonde
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Fukuchi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003072:Cognition Disorders / Q000503:physiopathology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D009154:Mutation; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D018925:Chemokines; D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4