The blood-brain barrier consists of specialized cells that line blood vessels passing through the brain. These cells collectively permit only certain molecules to pass to and from the brain, maintaining the distinct biochemistry and cell populations of the central nervous system versus the rest of the body. Where the blood-brain barrier leaks, the result is inflammation and dysfunction in brain tissue as, a reaction to the presence of unexpected and unwanted molecules and cells. Unfortunately the blood-brain barrier declines and malfunctions with age, as is the case for all complex biological systems. This is likely an important contribution to the development of neurodegenerative conditions.
In today's open access paper, researchers discuss the role of hypoxia in producing blood-brain barrier dysfunction. While a local lack of oxygen will induce leakage of the blood-brain barrier at any age, older individuals are both more vulnerable and more likely to suffer conditions and states of aging that provoke hypoxia on a regular basis. Greater blood-brain barrier leakage in transiently hypoxic individuals may be an important mechanism in the link between a number of hypoxia-inducing conditions and increased risk of neurodegenerative conditions.
Defining the hypoxic thresholds that trigger blood-brain barrier disruption: the effect of age
We recently demonstrated that exposure to chronic mild hypoxia (CMH; 8% O2) in young (2 months old) mice triggers a cerebrovascular remodeling response that includes endothelial proliferation and low levels of transient blood-brain barrier (BBB) disruption that is accompanied by microglial activation and aggregation around leaky blood vessels. Strikingly, the extent of hypoxia-induced BBB disruption is greatly amplified (5-10-fold) in aged (20 months old) mice. As hypoxia is a common component of many age-related diseases including chronic obstructive pulmonary disease (COPD), asthma, ischemic heart disease, heart failure, and sleep apnea, it follows that in the elderly population, hypoxic events could trigger BBB breakdown, culminating in neuronal dysfunction, neurodegeneration, and vascular dementia. Consistent with this idea, several studies have demonstrated increased dementia risk in people who suffer from hypoxia-inducing conditions such as sleep apnea and COPD.
What hypoxic level is sufficient to trigger vascular remodeling and BBB breakdown, and how does age influence the hypoxic threshold that triggers BBB disruption? At what age do cerebral blood vessels become more susceptible to hypoxia-induced disruption? In this study, we addressed these fundamental questions by first exposing young (2 months old) and aged (20 months old) mice to a range of oxygen levels from normoxia (21% O2) to marked hypoxia (8% O2) to define the hypoxic thresholds that triggers vascular remodeling and BBB disruption at the two different ages. Next, we investigated at what specific age mice become more susceptible to hypoxia, by comparing mice of 8 different ages (from 2 months to 23 months) to a fixed (8% O2) level of hypoxia.
Analysis of brain sections demonstrated that the thresholds required to trigger hypoxia-induced BBB disruption (CD31/fibrinogen) and endothelial proliferation (CD31/Ki67) were much lower in aged mice (15% O2) compared to young (13% O2). Hypoxia-induced endothelial proliferation was relatively constant across the age range, but advanced age strongly enhanced the degree of BBB disruption (4-6-fold greater in 23 months vs. 2 months old). While the BBB became more vulnerable to hypoxic disruption at 12-15 months, a large step-up also occurred at the surprisingly young age 2-6 months. Our data demonstrates that the aged BBB is far more sensitive to hypoxia-induced BBB disruption than the young and define the hypoxic thresholds that trigger hypoxia-induced BBB disruption in young and aged mice. This information has translational implications for people exposed to hypoxia and for those living with hypoxia-associated conditions such as asthma, emphysema, ischemic heart disease, and apnea.
View the full article at FightAging
