Yesterday I pointed out a prospective treatment that briefly disrupts the blood-brain barrier and by doing so appears to provoke glia, the immune cells of the brain, into clearing up amyloid deposits. The visible outcome is an improved state of cognitive function in a mouse model of Alzheimer's disease wherein the mice are engineered to generate amyloid in large amounts and show accelerated cognitive decline. That is one interpretation of the results, in any case. It is interesting that the researchers produced measurable benefits by temporarily opening the blood-brain barrier, as, like all structures in the body, its function declines and falters with age, and this is thought to contribute to neurodegenerative conditions such as Alzheimer's disease.
What is the blood-brain barrier? It is a layer of cells that wraps capillary blood vessels in the brain, wherein neighboring cell membranes overlap in an arrangement known as a tight junction that forms a barrier to fluids. It isn't just a wall, however: it is also a collection of molecular mechanisms that very selectively transport various privileged molecules back and forth between the brain and the blood supply. Everything else is blocked. With advancing age this barrier begins to leak, but the causes and mechanisms involved are not entirely clear at the detailed level, and nor is it completely nailed down as to exactly what sort of further damage is caused as a consequence of this leakage.
This open access paper on the topic is presently only available as a PDF, but is a good illustration of the current state of knowledge regarding the blood-brain barrier in aging: the sorts of questions that remain open and the direction of present research. As is often the case in specific manifestations of age-related degeneration, rising levels of chronic inflammation appear to play an important role:
An accumulating body of evidence suggests that disruption of blood-brain barrier (BBB) function followed by blood-to-brain extravasation of circulating neuroinflammatory molecules may increase risk for the onset and progress of cerebrovascular-based neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VaD) and multiple sclerosis. We recently reported in wild-type mice maintained on standard diets, progressive deterioration of capillary function with aging was concomitant with heightened neuroinflammation. However, the mice used in this study were relatively young (12 months of age) and potential mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular mechanisms.
A functional consequence of increased cerebral capillary permeability with aging is enhanced blood-to-brain delivery of circulating neuroinflammatory molecules. Disturbed BBB has been reported in mid-aged rodent models independent of co-morbidities or the provision of pro-inflammatory diets. The cerebrospinal fluid/serum ratio of albumin, a surrogate marker of increased capillary permeability, is significantly elevated with aging. In addition, recent studies suggest that increased BBB permeability in aged rodent brains is associated with reduced expression of BBB tight junction proteins.
Only a few studies have investigated potential mechanisms involved in BBB breakdown with normal aging and these suggest heightened inflammatory processes. In vitro and in vivo studies show that TNF-α potentiates the permeability of BBB by suppressing the expression of tight junction complexes, whilst inhibition of TNF-α results in restoration of the tight junction protein expression and normalized BBB integrity. Similarly, anti-TNF-α antibodies were shown to attenuate BBB permeability via restored expression of BBB tight junction proteins in rat model of acute liver failure. In this study, exaggerated endothelial TNF-α in aged mice was associated with reduced expression of the BBB tight junction proteins.
Collectively, the findings of this study suggest that the mechanisms of BBB dysfunction that occurs in normal aging may result from the loss of endothelial tight junctions, induced by pro-inflammatory TNF-α through heightened peripheral inflammation.