Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice.
Aging adversely affects inflammatory processes in the brain, which has important implications in the context of disease progression. It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we sought to characterize inflammatory changes in a mouse model of Alzheimer's disease and to delineate differences between normal aging and those associated with disease pathology. A proinflammatory profile, characterized by the upregulation of markers of classical activation, was evident in APPswe/PS1dE9 mice, associated with increased interferon-γ (IFNγ) concentration and dysregulation of mechanisms designed to limit the proinflammatory response. The data indicate that microglia are not less active with age but alter their phenotype; indeed, changes observed in the deactivation state appear to relate to aging rather than disease pathology. We hypothesize that disruption of the blood-brain barrier, in tandem with an enhanced chemokine profile, permits the infiltration of immune cells serving to reinforce classical activation of microglia through their enhanced responsiveness to IFNγ.
Institute of Neuroscience, Trinity College, Dublin, Ireland. Electronic address: aminogu@tcd.ie.
Aedín M
AM
Minogue
Institute of Neuroscience, Trinity College, Dublin, Ireland.
Raasay S
RS
Jones
Institute of Neuroscience, Trinity College, Dublin, Ireland.
Ronan J
RJ
Kelly
Institute of Neuroscience, Trinity College, Dublin, Ireland.
Claire L
CL
McDonald
Institute of Neuroscience, Trinity College, Dublin, Ireland.
Thomas J
TJ
Connor
Institute of Neuroscience, Trinity College, Dublin, Ireland.
Marina A
MA
Lynch
D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology*; D009154:Mutation; D010539:Permeability; D053764:Presenilin-1 / Q000235:genetics*; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D018836:Inflammation Mediators; D053764:Presenilin-1; D007371:Interferon-gamma
Alzheimer's disease; Blood-brain barrier permeability; Infiltrating immune cells; Interferon-γ; Microglial activation states