title: Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by β-amyloid oligomers in an acute mouse model of Alzheimer's disease.
abstract: BACKGROUND
  Amyloid-β oligomers (AβO) are species mainly involved in the synaptic and cognitive dysfunction in Alzheimer's disease. Although their action has been described mainly at neuronal level, it is now clear that glial cells govern synaptic activity in their resting state, contributing to new learning and memory establishment. In contrast, when activated, they may lead to synaptic and cognitive dysfunction. Using a reliable acute AβO-mediated mouse model of AD, we explored whether the memory alteration AβOs induce relies on the activation of glial cells, and if Toll-like receptor 4 (TLR4), pivotal in the initiation of an immune response, is involved.
  
  
  METHODS
  C57 naïve mice were given a single intracerebroventricular injection of synthetic AβO-containing solution (1μM), which induces substantial impairment in the establishment of recognition memory. Then, first we assessed glial cell activation at different times post-injection by western blot, immunohistochemistry and ELISA in the hippocampus. After that we explored the efficacy of pre-treatment with anti-inflammatory drugs (indomethacin and an IL-1β receptor antagonist) to prevent impairment in the novel object recognition task, and compared AβO's effects in TLR4 knockout mice.
  
  
  RESULTS
  A single AβO injection rapidly activated glial cells and increased pro-inflammatory cytokine expression. Both anti-inflammatory drugs prevented the AβO-mediated impairment in memory establishment. A selective TLR4 receptor antagonist abolished AβO's action on memory, and in TLR4 knockout mice it had no effect on either memory or glial activation.
  
  
  CONCLUSIONS
  These data provide new information on AβO's mechanism of action, indicating that besides direct action at the synapses, they also act through the immune system, with TLR4 playing a major role. This suggests that in a potential therapeutic setting inflammation must be considered as well.
authors.affiliation: Departments of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: claudia.balducci@marionegri.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Balducci
authors.affiliation: Departments of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: angelisa.frasca@gmail.com.
authors.forename: Angelisa
authors.initials: A
authors.lastname: Frasca
authors.affiliation: Departments of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: margheritazotti@virgilio.it.
authors.forename: Margherita
authors.initials: M
authors.lastname: Zotti
authors.affiliation: Departments of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: pietro.lavitola@marionegri.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: La Vitola
authors.affiliation: Department of Physiology and Pharmacology, La Sapienza University of Rome, 00185 Rome, Italy. Electronic address: emanuela.mhillaj@uniroma1.it.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mhillaj
authors.affiliation: Departments of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: e.grigoli89@gmail.com.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Grigoli
authors.affiliation: Departments of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: m.iacobellis1@campus.unimib.it.
authors.forename: Martina
authors.initials: M
authors.lastname: Iacobellis
authors.affiliation: Departments of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: federica.grandi@guest.marionegri.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Grandi
authors.affiliation: Departments of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: massimo.messa@humanitasresearch.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Messa
authors.affiliation: Departments of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: laura.colombo@marionegri.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.affiliation: Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy. Electronic address: monicamolteni65@gmail.com.
authors.forename: Monica
authors.initials: M
authors.lastname: Molteni
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy. Electronic address: luigia.trabace@unifg.it.
authors.forename: Luigia
authors.initials: L
authors.lastname: Trabace
authors.affiliation: Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy. Electronic address: Carlo.Rossetti@uninsubria.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rossetti
authors.affiliation: Departments of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: mario.salmona@marionegri.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Departments of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy. Electronic address: gianluigi.forloni@marionegri.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D060825:Cognitive Dysfunction / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D051197:Toll-Like Receptor 4
keywords: Alzheimer’s disease; Beta-amyloid oligomers; IL-1β; IL-1β receptor antagonist; Indomethacin; Memory impairment; Neuroinflammation; Novel object recognition test; Pro-inflammatory cytokines; Toll-like receptor 4