The Tight Junctions of the Blood-Brain Barrier in Aging and Neurodegeneration

Today's open access paper is a review of the tight junction structures of the blood-brain barrier in aging and neurodegeneration. The blood-brain barrier is a structure of specialized cells that lines the blood vessels that pass through central nervous system tissue. The barrier allows only certain molecules and cells to pass between blood vessels and the central nervous system, thus preserving its separation from the rest of the body. Unfortunately the integrity of the blood-brain barrier breaks down with advancing age, and the entry of unwanted molecules and cells into the brain then contributes to inflammation and tissue dysfunction.

A number of studies have shown links between blood-brain barrier dysfunction and the progression of neurodegenerative conditions. Researchers have identified leakage of fibrinogen into the brain as a cause of inflammation and synaptic damage. The inappropriate passage of molecules across the blood-brain barrier begins when the behavior of endothelial cells changes for the worse, and there is also a progressive loss in the number of pericyte cells. These changes correlates with cognitive decline even in the absence of other signs of pathology, such as protein aggregates. Interestingly, the amyloid-β characteristic of Alzheimer's disease has been shown to cause blood-brain barrier dysfunction.

The Blood-Brain Barrier and Its Intercellular Junctions in Age-Related Brain Disorders

The functional state of the central nervous system (CNS) is greatly dependent on the quality of the vasculature. As the centuries old saying goes: "A man is as old as his arteries". Today, especially for the brain, this concept should be redefined: You are as old as your microvessels and capillaries. There is increasing evidence that the cerebral microvasculature and the neurovascular unit play a critical role in age-related brain dysfunctions. The multitude of brain microvascular changes accompanied by aging includes endothelial dysfunction, blood-brain barrier (BBB) breakdown, decrease in blood flow, microhemorrhages, vessel rarefication, and neurovascular uncoupling.

Cerebral endothelial cells (CECs) lining brain capillaries are considered the principal barrier forming endothelial cells. They are interconnected by a continuous line of tight junctions and characterized by a high number of mitochondria and low number of caveolae. These characteristics contribute to the formation of a paracellular and transcellular barrier.

With aging, the density of brain vasculature is decreased and cerebrovascular dysfunction appears to precede and accompany cognitive dysfunction and neurodegeneration. Cerebrovascular angiogenesis is decreased and cerebral blood flow is inhibited by anomalous blood vessels such as tortuous arterioles and thick collagen deposits in the walls of veins and venules. In most mammals, the capacity of CECs to divide is limited and endothelial cells are prone to be senescent. Aging is associated with endothelial dysfunction, arterial stiffening, and remodeling, impaired angiogenesis, defective vascular repair and with an increasing prevalence of atherosclerosis. In the aging brain cerebral blood flow declines and perfusion pressure either is constant or increases.

The paracellular barrier properties of CECs are determined by the tight junction (TJ), which are composed of transmembrane proteins that control the transport across the intercellular space between adjacent cells and cytoplasmic plaque. Limited data is available on what changes develop in the function of the BBB and the composition and structure of endothelial TJs in the healthy aging human brain. In a meta-analysis of BBB permeability studies, the barrier function was negatively impacted by age. Though there were some discrepancies, paracellular permeability was generally increased in the aged human brain. Permeability changes are likely the result of decreased expression and disorganized localization of TJ proteins.

With the building evidence that dysfunction of the microvasculature is not just coincident but is part of the underlying mechanisms of aging and associated neurovascular and neurological disorders, new therapeutic possibilities are opened. The significant heterogeneity of BBB disruption data in studies using aging postmortem brain tissue suggests that more data is necessary to clearly understand the role of BBB disruption and to see whether it is a symptom or a cause. Thus further comprehensive BBB TJ and permeability studies are needed in the field of aging and aging associated disorders.

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