title: Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer's disease.
abstract: The effects of Toll-like receptor (TLR) activation in peripheral cells are well characterized but, although several TLRs are expressed on cells of the brain, the consequences of their activation on neuronal function remain to be fully investigated, particularly in the context of assessing their potential as therapeutic targets in neurodegenerative diseases. Several endogenous TLR ligands have been identified, many of which are soluble factors released from cells exposed to stressors. In addition, amyloid-β (Aβ) the main constituent of the amyloid plaques in Alzheimer's disease (AD), activates TLR2, although it has also been shown to bind to several other receptors. The objective of this study was to determine whether activation of TLR2 played a role in the developing inflammatory changes and Aβ accumulation in a mouse model of AD. Wild type and transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1 mice) were treated with anti-TLR2 antibody for 7months from the age of 7-14months. We demonstrate that microglial and astroglial activation, as assessed by MHCII, CD68 and GFAP immunoreactivity was decreased in anti-TLR2 antibody-treated compared with control (IgG)-treated mice. This was associated with reduced Aβ plaque burden and improved performance in spatial learning. The data suggest that continued TLR2 activation contributes to the developing neuroinflammation and pathology and may be provide a strategy for limiting the progression of AD.
authors.affiliation: Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Claire L
authors.initials: CL
authors.lastname: McDonald
authors.affiliation: Physical Therapy and Rehabilitation Science, Brain and Spinal Injury Center, University of California San Francisco, San Francisco General Hospital, 1001 Potrero av, Bld#1, Room#101, 94110 San Francisco, CA, United States.
authors.forename: Edel
authors.initials: E
authors.lastname: Hennessy
authors.affiliation: Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Ana
authors.initials: A
authors.lastname: Rubio-Araiz
authors.affiliation: Opsona Therapeutics LTD, 2nd Floor Ashford House, Tara Street, Dublin 2 D02 VX67, Ireland.
authors.forename: Brian
authors.initials: B
authors.lastname: Keogh
authors.affiliation: Immune Regulation Research Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, Ireland.
authors.forename: William
authors.initials: W
authors.lastname: McCormack
authors.affiliation: Opsona Therapeutics LTD, 2nd Floor Ashford House, Tara Street, Dublin 2 D02 VX67, Ireland.
authors.forename: Peter
authors.initials: P
authors.lastname: McGuirk
authors.affiliation: Opsona Therapeutics LTD, 2nd Floor Ashford House, Tara Street, Dublin 2 D02 VX67, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: Reilly
authors.affiliation: Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address: lynchma@tcd.ie.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Lynch
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001253:Astrocytes / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D053764:Presenilin-1; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C580804:presenilin 1, mouse
keywords: APP/PS1 mice; Alzheimer’s disease; Amyloid-β (Aβ); Astrocytic activation; Cognitive function; Microglial activation; Neuroinflammation; Toll-like receptor 2 (TLR2)