The \u03b1-dystrobrevins play a key role in maintaining the structure and function of the extracellular matrix\u2013significance for protein elimination failure arteriopathies

Matthew Macgregor Sharp,Masato Yasui,Yoichiro Abe,James Lyles,Roxana O Carare,Dariusz C Górecki,Abby Keable,Thomas Thornton,Roy O Weller,Maureen Gatherer,Shinsuke Shibata,Jordan Cassidy

doi:10.1186/s40478-021-01274-8

Abstract

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.

Highlights

Cerebral blood vessels serve a dual function; forming an essential component of the neuro-vascular unit to regulate cerebral blood flow [1] and providing extracellular matrix (ECM) pathways within the walls of capillaries, Sharp et al acta neuropathol commun (2021) 9:171 of capillaries in the parenchyma and continue towards the basement membranes surrounding smooth muscle cells in the arterioles and arteries, as intramural periarterial drainage (IPAD) [7, 10,11,12]
Pathological characteristics of Cerebral Amyloid Angiopathy (CAA) consist of the progressive accumulation of congophilic amyloid peptides of different amino acid lengths in the walls of leptomenigeal arteries, and in the walls of cortical arterioles and capillaries, very rarely affecting venules [13, 14]. Based on this pattern of amyloid deposition in both humans [13, 14] and transgenic mouse models, as well as experimental studies involving the study of drainage of tracers from the brain, it is recognised that a key mechanism for the development of CAA is the failure of clearance of amyloid along vascular basement membranes represented by IPAD [4, 15,16,17,18,19]
Expression of α‐DB at glial‐vascular endfeet is elevated in protein elimination failure arteriopathies To assess whether the positive correlation between dystrobrevin gene expression and protein elimination failure arteriopathies in human dementia cohorts previously reported in [44] could be associated with elevated expression of α-DB at glial-vascular endfeet, post-mortem occipital brain sections from young, old non-demented and severe CAA brains were immunostained for α-DB

Summary

Introduction

Cerebral blood vessels serve a dual function; forming an essential component of the neuro-vascular unit to regulate cerebral blood flow [1] and providing extracellular matrix (ECM) pathways within the walls of capillaries, Sharp et al acta neuropathol commun (2021) 9:171 of capillaries in the parenchyma and continue towards the basement membranes surrounding smooth muscle cells in the arterioles and arteries, as IPAD [7, 10,11,12] Failures in this process are linked to Protein Elimination Failure Arteriopathies, such as Cerebral Amyloid Angiopathy (CAA). AQP4 has been implicated in glymphatic/ convective influx of cerebrospinal fluid into the brain but its role in the tethering of astrocyte endfeet to the BM is unclear [31]

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Conclusion