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Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia.
Acta Neuropathol Commun. 2016 08 04; 4(1):76.AN

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+Show Affiliations

German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27487766

Citation

Saggu, Raman, et al. "Astroglial NF-kB Contributes to White Matter Damage and Cognitive Impairment in a Mouse Model of Vascular Dementia." Acta Neuropathologica Communications, vol. 4, no. 1, 2016, p. 76.
Saggu R, Schumacher T, Gerich F, et al. Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. Acta Neuropathol Commun. 2016;4(1):76.
Saggu, R., Schumacher, T., Gerich, F., Rakers, C., Tai, K., Delekate, A., & Petzold, G. C. (2016). Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. Acta Neuropathologica Communications, 4(1), 76. https://doi.org/10.1186/s40478-016-0350-3
Saggu R, et al. Astroglial NF-kB Contributes to White Matter Damage and Cognitive Impairment in a Mouse Model of Vascular Dementia. Acta Neuropathol Commun. 2016 08 4;4(1):76. PubMed PMID: 27487766.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. AU - Saggu,Raman, AU - Schumacher,Toni, AU - Gerich,Florian, AU - Rakers,Cordula, AU - Tai,Khalid, AU - Delekate,Andrea, AU - Petzold,Gabor C, Y1 - 2016/08/04/ PY - 2016/07/15/received PY - 2016/07/19/accepted PY - 2016/8/5/entrez PY - 2016/8/5/pubmed PY - 2017/10/27/medline KW - Astrocytes KW - Diffusion tensor imaging (DTI) KW - Glia KW - NF-kB KW - Neuroinflammation KW - vascular cognitive impairment SP - 76 EP - 76 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 4 IS - 1 N2 - 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. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/27487766/Astroglial_NF_kB_contributes_to_white_matter_damage_and_cognitive_impairment_in_a_mouse_model_of_vascular_dementia_ L2 - https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-016-0350-3 DB - PRIME DP - Unbound Medicine ER -