The impact of neurovascular, blood-brain barrier, and glymphatic dysfunction in neurodegenerative and metabolic diseases

Aug 3, 2020International review of neurobiology

Problems with brain blood flow, barrier, and waste clearance in brain and metabolic diseases

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Abstract

Dysfunction of the blood-brain barrier and blood-CSF barrier is reported in both rodent models and human subjects with Alzheimer's disease.

The cerebral vasculature facilitates nutrient and waste exchange in the brain.
The blood-brain barrier regulates the entry of molecules into brain tissue.
The neurovascular unit adjusts blood flow based on the brain's metabolic needs.
The glymphatic system is involved in fluid exchange and clearance of waste in the brain.
Dysfunctions in these barriers are associated with the development of neurodegenerative diseases.
Slowed clearance of proteins like amyloid β and tau in animal models may contribute to neurodegeneration.

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The cerebral vasculature serves as the crossroads of the CNS, supporting exchange of nutrients, metabolic wastes, solutes and cells between the compartments of the brain, including the blood, brain interstitium, and cerebrospinal fluid (CSF). The blood-brain barrier (BBB) regulates the entry and efflux of molecules into brain tissue. The cells of the neurovascular unit regulate cerebral blood flow, matching local metabolic demand to blood supply. The blood-CSF barrier at the choroid plexus secretes CSF, which supports the brain and provides a sink for interstitial solutes not cleared across the BBB. Recent studies have characterized the glymphatic system, a brain-wide network of perivascular spaces that supports CSF and interstitial fluid exchange and the clearance of interstitial solutes to the CSF. The critical role that these structures play in maintaining brain homeostasis is illustrated by the established and emerging roles that their dysfunctions play in the development of neurodegenerative diseases, such as Alzheimer's disease (AD). Loss of BBB and blood-CSF barrier function is reported both in rodent models of AD, and in human AD subjects. Cerebrovascular dysfunction and ischemic injury are well established contributors to both vascular dementia and to a large proportion of cases of sporadic AD. In animal models, the slowed glymphatic clearance of interstitial proteins, such as amyloid β or tau, are proposed to contribute to the development of neurodegenerative diseases, including AD. In total, these findings suggest that cellular and molecular changes occurring within and around the cerebral vasculature are among the key drivers of neurodegenerative disease pathogenesis.

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The impact of neurovascular, blood-brain barrier, and glymphatic dysfunction in neurodegenerative and metabolic diseases

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