The duality of the BBB: breaking the myth of the blood-brain barrier breakdown.

Research on the blood-brain barrier (BBB) has greatly evolved over the past 20 years, with growing recognition of its role as a multicellular complex regulating brain homeostasis. Previously confined to pharmaceutical sciences, the BBB has now become a growing focus of interest for neuroscientists and clinicians. However, the word ‘barrier’, implying something that can be broken, opened, or disrupted, can lead to confusion when one tries to relate this concept to its underlying cell biology. Here, echoing the fundamental question posed by Lina Stern when she first defined the BBB in 1921, I suggest that the confusion stems from conflating the physicochemical properties intrinsic to the barrier with the living biological multicellular interface. Notwithstanding its complexity, the BBB is now often simplistically portrayed as “permeable”, particularly in the context of prevalent diseases, such as Alzheimer’s, depression, multiple sclerosis, or stroke. Such overly simplified concepts promoted over the past two decades have led to misconceptions that hinder a proper understanding of the BBB, affecting both the general public and seasoned scientists. This misunderstanding is not without harmful clinical impact as many interpret the BBB as something that often breaks, leading to a massive entry of drugs and other blood-borne compounds into the brain, which is very rarely the case. After outlining the likely causes of these misconceptions and trying to define the concepts of “BBB permeability” and “brain bioavailability”, I offer several recommendations: (1) more frequent use of quantitative methods involving small hydrophilic compounds to measure BBB integrity; (2) avoid terms such as ‘BBB disruption,’ ‘opening,’ or ‘breakdown,’ and instead favor terms like ‘dysfunction’ or, where appropriate, ‘leakage’, essentially when describing biological defects assessed by changes in large molecule localization; and (3) always account for the dual nature of the BBB, as both a physicochemical barrier and a living biological interface.