Title:In Vivo Uptake of β-Amyloid by Non-Plaque Associated Microglia
VOLUME: 9 ISSUE: 8
Author(s):Cheryl A Hawkes, LeHua Deng, Daniela Fenili, Mark Nitz and JoAnne McLaurin
Affiliation:Centre for Research in Neurodegenerative Diseases, 6 Queen’s Park Crescent West, Toronto, Ontario, M5S 3H2, Canada.
Keywords:Alzheimer’s disease, anti-aggregant, transgenic mouse model, Microglia, Immunoblotting, Central nervous system, β-amyloid, Glial fibrillary acidic protein
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.
