Fight Aging!

The blood-brain barrier is a specialized layer of cells that wrap blood vessels passing through the central nervous system, ensuring that only certain molecules can pass in either direction. Thus the biochemistry of the central nervous system is kept distinct from that of the rest of the body. This separation is necessary for correct function, as illustrated by the point that the blood-brain barrier begins to break down with advancing age. This produces damage and dysfunction in the brain, as unwanted cells and molecules leak through the faulty blood-brain barrier. As noted here, however, the relative scope and size of this contribution to neurodegeneration, in comparison to other contributing factors, is far from fully determined.

Changes in the immune system have long been recognized to occur with aging, and it is now appreciated that neuroinflammation likely contributes to age-associated neurological diseases. However, it is less well understood how specific changes in the immune system with aging may affect central nervous system (CNS) functions and contribute to neurological disease. We posit that brain barriers, especially the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are important interfaces between CNS and peripheral tissues that are affected by age-associated changes in the immune system. The BBB/BCSFB may, in turn, affect homeostatic functions of the CNS, and/or exhibit more detrimental responses to pathological stimuli.

One of the most-studied (and yet, poorly understood) aspects of BBB dysfunction is disruption, which is typically defined by the apparent leakage of normally BBB impenetrant molecules. Recent imaging results argue that BBB disruption does occur in healthy aging, and is worse in individuals with mild cognitive impairment, which is considered a prodrome of Alzheimer's disease (AD). One common approach to proxy BBB disruption in living humans is to measure the ratio of abundant, BBB-impermeant proteins such as albumin or immunoglobulin G (IgG) in cerebrospinal fluid (CSF) versus serum. However, these measures may be confounded by other known CNS deficits with aging, such as altered production and reabsorption of CSF, and inflammatory changes in the serum and CSF levels of these proteins. Further, there may be leakage of the BCSFB and altered protein synthesis at this site with age. Recent studies have implemented advanced imaging technologies that can visualize leakage of intravenously injected tracers via dynamic contrast MRI, and these have indicated that vascular BBB disruption does occur in the aging human brain, albeit at low levels.

In healthy aged mice, leakage of IgG into the parenchymal space of the cerebral cortex and hippocampus occurs when compared with young mice, suggesting that there is BBB disruption in this model. Increased IgG leakage in aged mice was associated with astrogliosis, endoplasmic reticulum (ER) stress, and increased endothelial cell levels of TNF-α; the latter measure significantly correlated with circulating levels of IL-6. In the same study, a significant reduction in occludin expression per brain endothelial cell was also observed in aged mice. Other studies have corroborated findings of BBB disruption in aging mice. Molecular mechanisms of BBB disruption in aging have been identified, and include reduced expression of sirtuin-1, a de-acetylase enzyme which has been implicated in the regulation of lifespan, senescence, and inflammatory responses to environmental stress.

BBB disruption in the context of aging or disease could result in disease exacerbation through leakage of potentially harmful proteins into the brain. However, it is not entirely clear that BBB disruption under any circumstance will always lead to brain damage. For example, certain therapeutic strategies for delivery of chemotherapeutics to the brain have relied on transiently disrupting the BBB, and are generally well-tolerated when brain cancers are the target. Recent work has also indicated that repeated transient BBB disruption in humans with AD using focused ultrasound did not cause any serious clinical or radiological adverse events. In contrast, healthy rodents with no prior brain abnormalities showed symptoms of reactive gliosis and neurodegeneration when transiently perfused with mannitol to cause widespread disruption of the BBB, and also had increased deposition of harmful serum proteins like fibrinogen in the CNS. The apparent paradox in efforts to disrupt the BBB as a therapeutic strategy versus BBB disruption having known adverse consequences on the CNS and associations with many CNS diseases highlights the complexities of BEC barrier functions that are likely nuanced and context-specific. Why BBB disruption in and of itself is apparently innocuous under some conditions, but clearly detrimental in others remains to be understood in greater molecular detail.

Link: https://doi.org/10.3390/ijms20071632