title: Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia.
abstract: Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBα-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Raman
authors.initials: R
authors.lastname: Saggu
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Schumacher
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Gerich
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Rakers
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Khalid
authors.initials: K
authors.lastname: Tai
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Delekate
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. gabor.petzold@dzne.de.|Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. gabor.petzold@dzne.de.
authors.forename: Gabor C
authors.initials: GC
authors.lastname: Petzold
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology; D016893:Carotid Stenosis; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D015140:Dementia, Vascular / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology / Q000523:psychology; D003711:Demyelinating Diseases / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology / Q000523:psychology; D004195:Disease Models, Animal; D005911:Gliosis / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology / Q000523:psychology; D008297:Male; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066127:White Matter / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D000072000:NF-KappaB Inhibitor alpha
keywords: Astrocytes; Diffusion tensor imaging (DTI); Glia; NF-kB; Neuroinflammation; vascular cognitive impairment