Vascular dementia and failure of intramural periarterial drainage – the role of the dystrophin associated protein complex

Abstract

Introduction:
Cerebral small vessel disease (CSVD), a key aspect of vascular dementia (VaD), consists of pathological modifications to cerebral vessel walls and associated white matter lesions. Cerebral vessels have a dual function: perfusion of the brain and drainage of interstitial fluid and solutes along the walls of capillaries and arteries as Intramural Periarterial Drainage (IPAD). IPAD fails with age resulting in cerebral amyloid angiopathy (CAA), part of the spectrum of CSVD. Most animal models designed to study CAA are modified to overexpress amyloid proteins, but this is in contrast to the majority of CAA cases which occur due to a failure of clearance of soluble amyloid, rather than genetic mutations. The conduit for IPAD is the capillary and arterial basement membrane. This basement membrane is synthesised by cells of the vessel wall and its modification leads to a failure of IPAD and CAA. Polarised astrocytic extensions form end feet projections that encircle the abluminal side of the vessel wall attaching to basement membrane by the dystrophin associated protein complex (DPC), of which alpha dystrobrevin (α-DB) and aquaporin 4 (AQP4) are key components. Alterations to this complex disrupt the morphology of vessel walls, causing abnormalities to basement membranes and altering blood-brain barrier function.
This thesis aims to investigate the role of the DPC in the morphology and dynamics of IPAD pathways and to ascertain if mice with altered DPC can be used to model: 1) a failure of ISF fluid clearance by IPAD and 2) the features of CSVD and VaD. The following hypothesis are tested: 1) In mice that do not express glial AQP4 the morphology of capillary IPAD pathways is altered; 2) In mice genetically modified
for α-DB, the morphology and dynamics of IPAD pathways and cerebral perfusion are impaired.

Methods:
A detailed morphological study on the capillary wall from the white and grey matter in AQP4 and α-DB deficient mice was performed using quantitative electron microscopy and immunohistochemistry for collagen IV. The pattern of IPAD in white and grey matter was imaged and quantitatively measured in α-DB deficient and wild-type control mice. Cerebral perfusion under resting state and when challenged with hypercapnia was measured in α-DB deficient mice.

Results:
1) AQP4 deficient mice showed a reduction in the percentage surface area of basement membranes and an increase in the percentage surface area of intramural cells in the white matter. 2) In α-DB deficient mice, the percentage surface area occupied by basement membrane was increased in capillary walls in both grey and white matter, accompanied by an increased expression of collagen IV in the grey matter. 3) The pattern of IPAD in the grey matter of α-DB deficient mice showed fewer arterioles with fluorescent soluble Aβ in their walls compared to age matched controls. 4) Solutes from the normal white matter drain preferentially along the basement membranes of capillaries. 5) Absence of α-DB is associated with a normal perfusion but a lower capacity for adaptation to hypercapnia.

Conclusions.
The results highlight an important role for α-DB and the DPC in maintaining the structural integrity of basement membranes, which is reflected in the capacity for draining interstitial fluid and solutes via IPAD. The localisation of AQP4 to astrocyte endfeet by its indirect association with α-DB and the DPC is not critical for the morphology of the basement membrane in the grey matter. As the capillary walls in the grey matter appear normal and the intramural cells in the white matter are enlarged, in contrast to the findings in human disease, AQP4 deficient mice do not replicate features of CSVD and may not be a suitable model for mechanistic insights into CSVD or VaD. Since this work highlighted that IPAD occurs preferentially along the capillary walls in the normal white matter with little involvement from arteries, it is important to consider the failure of IPAD as a key mechanistic feature of white matter hyperintensities. It remains to be seen if there are changes to α-DB and the DPC in the spectrum of CSVD in human brains, as this work points to it as a suitable model for further hypothesis-based studies of CSVD.

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Identifiers

ORCID for Roxana-Octavia Carare: orcid.org/0000-0001-6458-3776

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