Interferon-{gamma} differentially affects Alzheimer's disease pathologies and induces neurogenesis in triple transgenic-AD mice.
Inflammatory processes, including the episodic and/ or chronic elaboration of cytokines, have been identified as playing key roles in a number of neurological disorders. Whether these activities impart a disease-resolving and/or contributory outcome depends at least in part on the disease context, stage of pathogenesis, and cellular milieu in which these factors are released. Interferon-gamma (IFNgamma) is one such cytokine that produces pleiotropic effects in the brain. It is protective by ensuring maintenance of virus latency after infection, yet deleterious by recruiting and activating microglia that secrete potentially damaging factors at sites of brain injury. Using the triple-transgenic mouse model of Alzheimer's disease (3xTg-AD), which develops amyloid and tau pathologies in a pattern reminiscent of human Alzheimer's disease, we initiated chronic intrahippocampal expression of IFNgamma through delivery of a serotype-1 recombinant adeno-associated virus vector (rAAV1-IFNgamma). Ten months of IFNgamma expression led to an increase in microglial activation, steady-state levels of proinflammatory cytokine and chemokine transcripts, and severity of amyloid-related pathology. In contrast, these rAAV1-IFNgamma-treated 3xTg-AD mice also exhibited diminished phospho-tau pathology and evidence of increased neurogenesis. Overall, IFNgamma mediates what seem to be diametrically opposed functions in the setting of AD-related neurodegeneration. Gaining an understanding as to how these apparently divergent functions are interrelated and controlled could elucidate new therapeutic strategies designed to harness the neuroprotective activity of IFNgamma.
Mastrangelo
Michael A
MA
Center for Neural Development and Disease, University of Rochester Medical Center, NY 14642, USA.
Sudol
Kelly L
KL
Narrow
Wade C
WC
Bowers
William J
WJ
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D011993:Recombinant Fusion Proteins; D016875:tau Proteins; D007371:Interferon-gamma