Pathology of the neurovascular unit in leukodystrophies

Abstract

The blood–brain barrier is a dynamic endothelial cell barrier in the brain microvasculature that separates the blood from the brain parenchyma. Specialized brain endothelial cells, astrocytes, neurons, microglia and pericytes together compose the neurovascular unit and interact to maintain blood–brain barrier function. A disturbed brain barrier function is reported in most common neurological disorders and may play a role in disease pathogenesis. However, a comprehensive overview of how the neurovascular unit is affected in a wide range of rare disorders is lacking. Our aim was to provide further insights into the neuropathology of the neurovascular unit in leukodystrophies to unravel its potential pathogenic role in these diseases. Leukodystrophies are monogenic disorders of the white matter due to defects in any of its structural components. Single leukodystrophies are exceedingly rare, and availability of human tissue is unique. Expression of selective neurovascular unit markers such as claudin-5, zona occludens 1, laminin, PDGFRβ, aquaporin-4 and α-dystroglycan was investigated in eight different leukodystrophies using immunohistochemistry. We observed tight junction rearrangements, indicative of endothelial dysfunction, in five out of eight assessed leukodystrophies of different origin and an altered aquaporin-4 distribution in all. Aquaporin-4 redistribution indicates a general astrocytic dysfunction in leukodystrophies, even in those not directly related to astrocytic pathology or without prominent reactive astrogliosis. These findings provide further evidence for dysfunction in the orchestration of the neurovascular unit in leukodystrophies and contribute to a better understanding of the underlying disease mechanism.

The neurovascular unit in leukodystrophies: towards solving the puzzle

“…ET-1 is upregulated in the WM astrocytes of CARASAL patients and results in dysregulation of the developmental programming of oligodendrocyte progenitor cells (OPCs) in the subventricular zone (SVZ) [132]. Further astrocytic involvement has been shown in a recent study that demonstrates the redistribution of AQP4 [45]. This indicates that also ion-water homeostasis in CARASAL could be disrupted.…”

“…Also, redistribution of ZO-1 indicates that BECs are dysfunctional. Whether this is a direct consequence of astrocytic dysfunction is still unclear [45]. Neuroinflammation conceivably also plays an important role in the pathology of AxD as perivascular lymphocytic infiltrates have been reported [70][71][72][73].…”

“…Microglia depletion is also seen, together with lipidladen macrophages and pigmented glia [97][98][99]. Reactive gliosis is observed in the WM together with AQP4 redistribution, indicating astrocytic involvement in the pathology [45]. CSF1R is a tyrosine kinase receptor crucial for the functioning of microglia.…”

“…Negative correlation between increased demyelination and reactive gliosis in the CNS Redistribution of AQP4 in frontal WM. Lipid-laden macrophages in perivascular space of WM can release inflammatory mediators [ 45 , 55 – 58 , 199 – 202 ] Myelin vacuolization LARS2- related leukodystrophy N/A LARS2 Astrocytes Deafness early in life and developmental delay Diffusely abnormal cerebral WM and elevated brain lactate levels on magnetic resonance spectroscopy Yes Enlarged lateral ventricles and rarefaction to cystic degeneration of the periventricular WM. U-fibres are spared Loss of myelin and reactive astrocytes at the vasculature Redistribution of ZO-1 and AQP4.…”

“…Especially when looking at heterogeneous diseases, such as leukodystrophies, certain features, such as BBB leakage of smaller molecules/ions and structural changes in the brain vasculature, can be overlooked. We recent showed that there is NVU involvement in different leukodystrophies regardless of MRI contrast enhancement or the main cellular component involved in the disease [ 45 ]. Furthermore, the tools to study these rare diseases are limited and rely mostly on clinical studies and post-mortem brain tissue.…”