The α-dystrobrevins play a key role in maintaining the structure and function of the extracellular matrix-significance for protein elimination failure arteriopathies.

Autor: Sharp MM; Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK., Cassidy J; Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK., Thornton T; Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK., Lyles J; Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK., Keable A; Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK., Gatherer M; Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK., Yasui M; Keio University School of Medicine, Tokyo, Japan., Abe Y; Keio University School of Medicine, Tokyo, Japan., Shibata S; Keio University School of Medicine, Tokyo, Japan., Weller RO; Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK., Górecki DC; Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, England.; Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-001, Warsaw, Poland., Carare RO; Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. rcn@soton.ac.uk.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2021 Oct 21; Vol. 9 (1), pp. 171. Date of Electronic Publication: 2021 Oct 21.
DOI: 10.1186/s40478-021-01274-8
Abstrakt: The extracellular matrix (ECM) of the cerebral vasculature provides a pathway for the flow of interstitial fluid (ISF) and solutes out of the brain by intramural periarterial drainage (IPAD). Failure of IPAD leads to protein elimination failure arteriopathies such as cerebral amyloid angiopathy (CAA). The ECM consists of a complex network of glycoproteins and proteoglycans that form distinct basement membranes (BM) around different vascular cell types. Astrocyte endfeet that are localised against the walls of blood vessels are tethered to these BMs by dystrophin associated protein complex (DPC). Alpha-dystrobrevin (α-DB) is a key dystrophin associated protein within perivascular astrocyte endfeet; its deficiency leads to a reduction in other dystrophin associated proteins, loss of AQP4 and altered ECM. In human dementia cohorts there is a positive correlation between dystrobrevin gene expression and CAA. In the present study, we test the hypotheses that (a) the positive correlation between dystrobrevin gene expression and CAA is associated with elevated expression of α-DB at glial-vascular endfeet and (b) a deficiency in α-DB results in changes to the ECM and failure of IPAD. We used human post-mortem brain tissue with different severities of CAA and transgenic α-DB deficient mice. In human post-mortem tissue we observed a significant increase in vascular α-DB with CAA (CAA vrs. Old p < 0.005, CAA vrs. Young p < 0.005). In the mouse model of α-DB deficiency, there was early modifications to vascular ECM (collagen IV and BM thickening) that translated into reduced IPAD efficiency. Our findings highlight the important role of α-DB in maintaining structure and function of ECM, particularly as a pathway for the flow of ISF and solutes out of the brain by IPAD.
(© 2021. The Author(s).)
Databáze: MEDLINE
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