Blood-Brain Barrier Dysfunction in Normal Aging and Neurodegeneration: Mechanisms, Impact, and Treatments

Abstract

Cerebral endothelial cells and their linking tight junctions form a unique, dynamic and multi-functional interface, the blood-brain barrier (BBB). The endothelium is regulated by perivascular cells and components forming the neurovascular unit. This review examines BBB and neurovascular unit changes in normal aging and in neurodegenerative disorders, particularly focusing on Alzheimer disease, cerebral amyloid angiopathy and vascular dementia. Increasing evidence indicates BBB dysfunction contributes to neurodegeneration. Mechanisms underlying BBB dysfunction are outlined (endothelium and neurovascular unit mediated) as is the BBB as a therapeutic target including increasing the uptake of systemically delivered therapeutics across the BBB, enhancing clearance of potential neurotoxic compounds via the BBB, and preventing BBB dysfunction. Finally, a need for novel biomarkers of BBB dysfunction is addressed.

Hypertension: Causes and Consequences of Circadian Rhythms in Blood Pressure

“…So that the brain can function despite the presence of a BBB, essential molecules or proteins cross the BBB and enter the cerebrospinal fluid (CSF) via an array of molecular transporters (eg, efflux and solute carriers) and receptors. [246][247][248][249] BBB function is facilitated by support cells, particularly perivascular astrocytes and capillary pericytes. 247 In relation to disease, a progressive decline in BBB function occurs normally with aging, 247 a change that can be accelerated by the presence of hypertension.…”

“…246–249 BBB function is facilitated by support cells, particularly perivascular astrocytes and capillary pericytes. 247…”

“…[246][247][248][249] BBB function is facilitated by support cells, particularly perivascular astrocytes and capillary pericytes. 247 In relation to disease, a progressive decline in BBB function occurs normally with aging, 247 a change that can be accelerated by the presence of hypertension. 250 This functional decline is believed to contribute to cognitive deficits, vascular dementia, and Alzheimer disease.…”

“…250 This functional decline is believed to contribute to cognitive deficits, vascular dementia, and Alzheimer disease. 247 Based on limited data, changes in daily rhythms in BP and BP variability have been associated with loss of BBB integrity in humans. 251 Loss of BBB integrity during atrial fibrillation or heart failure may contribute to the increased risk of dementia that is often associated with cardiac disease.…”

Vascular Biology of Dementia

“…Recent studies suggest a critical role for capillary and BBB dysfunction in CSVD-related dementia. The article by Andjelkovic et al 5 provides a comprehensive overview of changes in the BBB and their underlying mechanisms and impact on cognitive function in normal aging and neurodegenerative diseases, including VCID. The article discusses the specific roles of individual components of BBB, including endothelial cell mechanisms, neurovascular unit remodeling, and changes in endothelial cell glycocalyx, basement membrane and interstitial extracellular matrix that affect BBB and contribute to aging- and disease related cognitive dysfunction.…”