title: In vivo uptake of β-amyloid by non-plaque associated microglia.
abstract: The role of microglia in β-amyloid (Aβ) deposition or clearance in the Alzheimer's disease (AD) brain remains unclear. Previous in vivo studies have focused primarily on the association of microglia with Aβ-positive parenchymal plaques, but have given little consideration to the possible interaction between Aβ and non-plaque associated microglia. Further, it is not known if microglia play a direct role in mediating Aβ uptake following anti-aggregant treatment. We report here the identification of Aβ-positive processes throughout the cortex and hippocampus of TgCRND8 mice expressing the human Swedish (KM670/671NL) and Indiana (V717F) amyloid precursor protein mutations, which localized to ionized calcium binding protein-1-positive resident microglia that were not associated with extracellular plaques. Oral administration of 1-deoxy-1-fluoro-scyllo-inositol, a scyllo-inositol analogue, to TgCRND8 mice improved spatial memory impairments and suppressed amyloid pathology in a dose-dependent manner. Further, treatment with 1-deoxy-1- fluoro-scyllo-inositol significantly increased hippocampal intra-microglial Aβ levels without stimulating microglial proliferation or peripheral macrophage recruitment. These results reveal a novel, beneficial role for non-plaque associated microglia in the regulation of cerebral Aβ levels in a mouse model of AD.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hawkes
authors.forename: LeHua
authors.initials: L
authors.lastname: Deng
authors.forename: Daniela
authors.initials: D
authors.lastname: Fenili
authors.forename: Mark
authors.initials: M
authors.lastname: Nitz
authors.forename: JoAnne
authors.initials: J
authors.lastname: McLaurin
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007294:Inositol / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; C009217:scyllitol; D007294:Inositol