Jerome Badaut and colleagues suggest using the term “blood-brain border” rather than “blood-brain barrier,” being kind in that the acronym BBB need not be abandoned. I must agree that I welcome this change in terminology.
With our own work in using low-intensity ultrasound to overcome the blood-brain barrier (old terminology) for drug delivery, I find myself guilty in initially only thinking of this interface as being formed by tight junctions that form cis and trans interactions and need to be separated in order to allow for a more efficient drug uptake by the brain. In tissue culture systems, readings of the transepithelial/endothelial electrical resistance (TEER) are used to assess the leakiness of the barrier (separation of tight junctions); however, this reading does not factor in that low-intensity ultrasound also facilitates caveolin-mediated trans-cytoplasmic transport, and furthermore leads to the formation of pores and tunnels through which the exchange of cargoes can occur.
Another point in the context of Alzheimer’s disease is the ongoing discussion whether in AD the barrier is more leaky, or in fact becomes tighter as disease progresses and individuals age. Here, again the term "blood-brain border" would more accurately reflect the actual situation. Ryan Watts and colleagues had argued several years back that there is a lack of widespread blood-brain barrier disruption in AD, whereas the team of Berislav Zlokovic argued in multiple studies for the opposite. In my view, an illuminating paper was then published by Tony Wyss-Coray’s team who showed in mice that, while plasma proteins readily permeate the healthy brain parenchyma, their uptake is diminished in the aged brain, “driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis.”
A third aspect touched upon in Dr. Badaut’s article are differences at the BBB between brain areas. In fact, a widespread misconception of the brain is the idea that in a healthy person the brain is completely sealed off from the periphery whereas in a diseased situation it becomes leaky. This black-and-white thinking is incorrect, as even in a healthy brain, 0.1 percent of a peripherally administered antibody can enter the brain, with obvious relevance for immunotherapies. With its seven circumventricular organs that differ in their "border" function, the brain is a complex beast that cannot be perceived as a uniform barrier.
Together, I welcome the proposed change in terminology from barrier to border and aim to adopt this wording in our future manuscripts.
References:
Beekers I, Langeveld SA, Meijlink B, van der Steen AF, de Jong N, Verweij MD, Kooiman K.
Internalization of targeted microbubbles by endothelial cells and drug delivery by pores and tunnels.
J Control Release. 2022 Jul;347:460-475. Epub 2022 May 19
PubMed.
Bien-Ly N, Boswell CA, Jeet S, Beach TG, Hoyte K, Luk W, Shihadeh V, Ulufatu S, Foreman O, Lu Y, DeVoss J, van der Brug M, Watts RJ.
Lack of Widespread BBB Disruption in Alzheimer's Disease Models: Focus on Therapeutic Antibodies.
Neuron. 2015 Oct 21;88(2):289-97.
PubMed.
Yang AC, Stevens MY, Chen MB, Lee DP, Stähli D, Gate D, Contrepois K, Chen W, Iram T, Zhang L, Vest RT, Chaney A, Lehallier B, Olsson N, du Bois H, Hsieh R, Cropper HC, Berdnik D, Li L, Wang EY, Traber GM, Bertozzi CR, Luo J, Snyder MP, Elias JE, Quake SR, James ML, Wyss-Coray T.
Physiological blood-brain transport is impaired with age by a shift in transcytosis.
Nature. 2020 Jul 1;
PubMed.
Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV.
Blood-Brain Barrier: From Physiology to Disease and Back.
Physiol Rev. 2019 Jan 1;99(1):21-78.
PubMed.
Pfau SJ, Langen UH, Fisher TM, Prakash I, Nagpurwala F, Lozoya RA, Lee WA, Wu Z, Gu C.
Characteristics of blood-brain barrier heterogeneity between brain regions revealed by profiling vascular and perivascular cells.
Nat Neurosci. 2024 Oct;27(10):1892-1903. Epub 2024 Aug 29
PubMed.
Pandit R, Koh WK, Sullivan RK, Palliyaguru T, Parton RG, Götz J.
Role for caveolin-mediated transcytosis in facilitating transport of large cargoes into the brain via ultrasound.
J Control Release. 2020 Nov 10;327:667-675. Epub 2020 Sep 10
PubMed.
Comments
The University of Queensland
Jerome Badaut and colleagues suggest using the term “blood-brain border” rather than “blood-brain barrier,” being kind in that the acronym BBB need not be abandoned. I must agree that I welcome this change in terminology.
With our own work in using low-intensity ultrasound to overcome the blood-brain barrier (old terminology) for drug delivery, I find myself guilty in initially only thinking of this interface as being formed by tight junctions that form cis and trans interactions and need to be separated in order to allow for a more efficient drug uptake by the brain. In tissue culture systems, readings of the transepithelial/endothelial electrical resistance (TEER) are used to assess the leakiness of the barrier (separation of tight junctions); however, this reading does not factor in that low-intensity ultrasound also facilitates caveolin-mediated trans-cytoplasmic transport, and furthermore leads to the formation of pores and tunnels through which the exchange of cargoes can occur.
Another point in the context of Alzheimer’s disease is the ongoing discussion whether in AD the barrier is more leaky, or in fact becomes tighter as disease progresses and individuals age. Here, again the term "blood-brain border" would more accurately reflect the actual situation. Ryan Watts and colleagues had argued several years back that there is a lack of widespread blood-brain barrier disruption in AD, whereas the team of Berislav Zlokovic argued in multiple studies for the opposite. In my view, an illuminating paper was then published by Tony Wyss-Coray’s team who showed in mice that, while plasma proteins readily permeate the healthy brain parenchyma, their uptake is diminished in the aged brain, “driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis.”
A third aspect touched upon in Dr. Badaut’s article are differences at the BBB between brain areas. In fact, a widespread misconception of the brain is the idea that in a healthy person the brain is completely sealed off from the periphery whereas in a diseased situation it becomes leaky. This black-and-white thinking is incorrect, as even in a healthy brain, 0.1 percent of a peripherally administered antibody can enter the brain, with obvious relevance for immunotherapies. With its seven circumventricular organs that differ in their "border" function, the brain is a complex beast that cannot be perceived as a uniform barrier.
Together, I welcome the proposed change in terminology from barrier to border and aim to adopt this wording in our future manuscripts.
References:
Beekers I, Langeveld SA, Meijlink B, van der Steen AF, de Jong N, Verweij MD, Kooiman K. Internalization of targeted microbubbles by endothelial cells and drug delivery by pores and tunnels. J Control Release. 2022 Jul;347:460-475. Epub 2022 May 19 PubMed.
Bien-Ly N, Boswell CA, Jeet S, Beach TG, Hoyte K, Luk W, Shihadeh V, Ulufatu S, Foreman O, Lu Y, DeVoss J, van der Brug M, Watts RJ. Lack of Widespread BBB Disruption in Alzheimer's Disease Models: Focus on Therapeutic Antibodies. Neuron. 2015 Oct 21;88(2):289-97. PubMed.
Yang AC, Stevens MY, Chen MB, Lee DP, Stähli D, Gate D, Contrepois K, Chen W, Iram T, Zhang L, Vest RT, Chaney A, Lehallier B, Olsson N, du Bois H, Hsieh R, Cropper HC, Berdnik D, Li L, Wang EY, Traber GM, Bertozzi CR, Luo J, Snyder MP, Elias JE, Quake SR, James ML, Wyss-Coray T. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature. 2020 Jul 1; PubMed.
Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-Brain Barrier: From Physiology to Disease and Back. Physiol Rev. 2019 Jan 1;99(1):21-78. PubMed.
Pfau SJ, Langen UH, Fisher TM, Prakash I, Nagpurwala F, Lozoya RA, Lee WA, Wu Z, Gu C. Characteristics of blood-brain barrier heterogeneity between brain regions revealed by profiling vascular and perivascular cells. Nat Neurosci. 2024 Oct;27(10):1892-1903. Epub 2024 Aug 29 PubMed.
Pandit R, Koh WK, Sullivan RK, Palliyaguru T, Parton RG, Götz J. Role for caveolin-mediated transcytosis in facilitating transport of large cargoes into the brain via ultrasound. J Control Release. 2020 Nov 10;327:667-675. Epub 2020 Sep 10 PubMed.
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