Blood vessels in the brain have properties that limit their permeability to ions, molecules, and cells circulating throughout the rest of the body; this is known as the blood–brain barrier (BBB). Not only is the BBB crucial for proper neuronal function and protecting the brain from harm — it is also a major impediment to drug delivery; hence, the relevance to the theme of gene-environment interactions. If the “environment” (any extracellular foreign chemical or endogenous compound) intends to send a signal to the brain (following which genes in the brain respond), that signal outside the brain must be capable of traversing the BBB.
Common folklore has suggested that the BBB becomes more permeable with age, but authors [see attached article & editorial] have found just the opposite; the BBB allows blood-borne proteins to enter the healthy brain at a much higher rate than previously thought, whereas the overall amount of plasma proteins entering the brain actually decreases with age. This finding might help researchers to understand [a] how the brain responds to systemic protein signals, and [b] the role of the BBB in age-related cognitive decline; this finding might also lead to improved approaches for delivering
drugs into the brain.
The BBB has many dynamic properties — physical, transport, immune, and more — that together tightly regulate movement of molecules between the blood and brain, thus controlling the brain’s molecular environment. A key question is therefore: what exactly does get across the BBB? Authors addressed this by examining how proteins found in blood plasma enter the brain. Whereas previous studies have traced the movement of injected exogenous proteins (i.e. those not native to the animal), authors [see attached article] labeled endogenous mouse plasma proteins and then injected them back into mice; in this way, they could track the movement of proteins that normally interact with the mouse BBB.
It was found that, in healthy young adult mice, a much higher quantity of plasma proteins (than previously thought) enters the brain, and therefore has the potential to interact with the neuronal circuitry (suggesting that a wide variety of neural functions — including mood and behavior — could be modulated by systemic protein signals). Moreover, authors showed that the amount of plasma protein that permeates the brain is less in old, than in young, mice (this discovery was surprising because multiple studies that had used exogenous tracers have shown that BBB permeability increases with age, and have suggested that this increase is likely a contributing factor to age-related cognitive decline).
However, authors demonstrated age-related changes — in the mechanism by which proteins are transported across the endothelial cells that line blood vessels of the BBB. In young adults, the predominant method of transport involves the binding of specific proteins to plasma-membrane receptors on endothelial cells; these receptors become incorporated into vesicles and are transported across the cell (a process called receptor-mediated transcytosis). In aged mice, receptor-mediated transcytosis is significantly decreased and non-receptor-mediated (nonspecific) transcytosis is increased, leading to nonspecific entry of a larger variety of plasma proteins into the old brain (previous studies, using exogenous molecules, probably measured only nonspecific transcytosis, thus missing the vast majority of plasma-protein permeation into the young brain). The finding — that the specificity of protein entry diminishes with age — could thus indicate that “aging alters the brain’s ability to receive specific plasma-protein signals.” 😉
Nature 16 Jul 2020; 583: 425-430 & editorial pp 362-363