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Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease.
Brain. 2015 Dec; 138(Pt 12):3716-33.B

Abstract

Reduced cerebral blood flow impairs cognitive function and ultimately causes irreparable damage to brain tissue. The gliovascular unit, composed of neural and vascular cells, assures sufficient blood supply to active brain regions. Astrocytes, vascular smooth muscle cells, and pericytes are important players within the gliovascular unit modulating vessel diameters. While the importance of the gliovascular unit and the signals involved in regulating local blood flow to match neuronal activity is now well recognized, surprisingly little is known about this interface in disease. Alzheimer's disease is associated with reduced cerebral blood flow. Here, we studied how the gliovascular unit is affected in a mouse model of Alzheimer's disease, using a combination of ex vivo and in vivo imaging approaches. We specifically labelled vascular amyloid in living mice using the dye methoxy-XO4. We elicited vessel responses ex vivo using either pharmacological stimuli or cell-specific calcium uncaging in vascular smooth muscle cells or astrocytes. Multi-photon in vivo imaging through a cranial window allowed us to complement our ex vivo data in the presence of blood flow after label-free optical activation of vascular smooth muscle cells in the intact brain. We found that vascular amyloid deposits separated astrocyte end-feet from the endothelial vessel wall. High-resolution 3D images demonstrated that vascular amyloid developed in ring-like structures around the vessel circumference, essentially forming a rigid cast. Where vascular amyloid was present, stimulation of astrocytes or vascular smooth muscle cells via ex vivo Ca(2+) uncaging or in vivo optical activation produced only poor vascular responses. Strikingly, vessel segments that were unaffected by vascular amyloid responded to the same extent as vessels from age-matched control animals. We conclude that while astrocytes can still release vasoactive substances, vascular amyloid deposits render blood vessels rigid and reduce the dynamic range of affected vessel segments. These results demonstrate a mechanism that could account in part for the reduction in cerebral blood flow in patients with Alzheimer's disease.media-1vid110.1093/brain/awv327_video_abstractawv327_video_abstract.

Authors+Show Affiliations

1 Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA 2 Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.1 Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA 2 Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.1 Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA 3 Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA 4 Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA sontheimer@vt.edu eroberson@uab.edu.1 Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA 2 Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL, USA sontheimer@vt.edu eroberson@uab.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

Language

eng

PubMed ID

26598495

Citation

Kimbrough, Ian F., et al. "Vascular Amyloidosis Impairs the Gliovascular Unit in a Mouse Model of Alzheimer's Disease." Brain : a Journal of Neurology, vol. 138, no. Pt 12, 2015, pp. 3716-33.
Kimbrough IF, Robel S, Roberson ED, et al. Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain. 2015;138(Pt 12):3716-33.
Kimbrough, I. F., Robel, S., Roberson, E. D., & Sontheimer, H. (2015). Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain : a Journal of Neurology, 138(Pt 12), 3716-33. https://doi.org/10.1093/brain/awv327
Kimbrough IF, et al. Vascular Amyloidosis Impairs the Gliovascular Unit in a Mouse Model of Alzheimer's Disease. Brain. 2015;138(Pt 12):3716-33. PubMed PMID: 26598495.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. AU - Kimbrough,Ian F, AU - Robel,Stefanie, AU - Roberson,Erik D, AU - Sontheimer,Harald, Y1 - 2015/11/23/ PY - 2015/02/26/received PY - 2015/08/24/accepted PY - 2015/11/25/entrez PY - 2015/11/26/pubmed PY - 2016/5/5/medline KW - Alzheimer’s disease KW - amyloidosis KW - multi-photon imaging KW - neurovascular coupling KW - vascular amyloid SP - 3716 EP - 33 JF - Brain : a journal of neurology JO - Brain VL - 138 IS - Pt 12 N2 - Reduced cerebral blood flow impairs cognitive function and ultimately causes irreparable damage to brain tissue. The gliovascular unit, composed of neural and vascular cells, assures sufficient blood supply to active brain regions. Astrocytes, vascular smooth muscle cells, and pericytes are important players within the gliovascular unit modulating vessel diameters. While the importance of the gliovascular unit and the signals involved in regulating local blood flow to match neuronal activity is now well recognized, surprisingly little is known about this interface in disease. Alzheimer's disease is associated with reduced cerebral blood flow. Here, we studied how the gliovascular unit is affected in a mouse model of Alzheimer's disease, using a combination of ex vivo and in vivo imaging approaches. We specifically labelled vascular amyloid in living mice using the dye methoxy-XO4. We elicited vessel responses ex vivo using either pharmacological stimuli or cell-specific calcium uncaging in vascular smooth muscle cells or astrocytes. Multi-photon in vivo imaging through a cranial window allowed us to complement our ex vivo data in the presence of blood flow after label-free optical activation of vascular smooth muscle cells in the intact brain. We found that vascular amyloid deposits separated astrocyte end-feet from the endothelial vessel wall. High-resolution 3D images demonstrated that vascular amyloid developed in ring-like structures around the vessel circumference, essentially forming a rigid cast. Where vascular amyloid was present, stimulation of astrocytes or vascular smooth muscle cells via ex vivo Ca(2+) uncaging or in vivo optical activation produced only poor vascular responses. Strikingly, vessel segments that were unaffected by vascular amyloid responded to the same extent as vessels from age-matched control animals. We conclude that while astrocytes can still release vasoactive substances, vascular amyloid deposits render blood vessels rigid and reduce the dynamic range of affected vessel segments. These results demonstrate a mechanism that could account in part for the reduction in cerebral blood flow in patients with Alzheimer's disease.media-1vid110.1093/brain/awv327_video_abstractawv327_video_abstract. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/26598495/Vascular_amyloidosis_impairs_the_gliovascular_unit_in_a_mouse_model_of_Alzheimer's_disease_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awv327 DB - PRIME DP - Unbound Medicine ER -