THE BLOOD-BRAIN BARRIER IS HIGHLY SPECIALIZED TO PROTECT THE BRAIN

D. Kempuraj^*

Research Laboratory at the Institute for Neuroimmune Medicine, Nova Southeastern University, Florida, USA.

*Correspondence to:
Duraisamy Kempuraj,
Research Laboratory at the Institute for Neuroimmune Medicine,
Nova Southeastern University,
Florida, USA.
e-mail: duraisamyk@health.missouri.edu

Received: 19 September, 2025 Accepted: 28 November, 2025

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2025 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

The blood-brain barrier (BBB) is semipermeable and is composed of cells that, under physiological conditions, prevent the passage of toxic substances and microorganisms into the brain. The BBB only allows passage of small molecules such as oxygen, glucose, and certain amino acids necessary for the physiological functioning of the brain. Glucose passes between endothelial cells via glucose transporter (GLUT) 1, a transporter protein that is expressed by both endothelia and astrocytes. This transport function occurs through passive diffusion and without the consumption of ATP. Various microorganisms, including viruses, bacteria, fungi, and parasites, can infect the brain by bypassing the BBB using specific strategies. Abnormal functioning of the BBB is a characteristic feature of neurodegenerative diseases, where it occurs consequentally following brain pathology and contributes to the progression of neurodegeneration.

KEYWORDS: Blood-brain barrier, brain, central nervous system, microorganism, glucose transporter, GLUT1

INTRODUCTION

The blood-brain barrier (BBB) is highly specialized in selectively preventing the passage of harmful substances into the central nervous system (CNS). The BBB is semipermeable and composed of vascular endothelial cells that prevent toxins, microorganisms, and other toxic compounds from entering the brain. The BBB is a lipophilic and dynamic barrier critical for maintaining homeostasis in the CNS microenvironment (1). The BBB is highly specialized for selectively preventing the exchange of neurotoxic molecules and regulating molecular trafficking (2). It supplies the brain with nutrients, key substrates for DNA and RNA synthesis, and regulatory molecules, and removes metabolic waste products into the blood (3).

BBB dysfunction often occurs in neurodegenerative diseases, such as Alzheimer’s disease (AD), where it is often observed early (4). The loss of pericytes in the BBB, along with reduced levels of glucose transporter (GLUT), leads to metabolic stress in the brain.

The endothelial cells of the cerebral capillaries are joined by tight junctions, including claudins and occludins that prevent the passage of harmful molecules, whose function is to protect the brain from substances circulating in the peripheral blood (5).

DISCUSSION

The BBB protects the brain from fluctuations in blood composition, while allowing the entry of nutrients and gases necessary for neuronal function (6). Additionally, the BBB allows the passage of substances such as oxygen, glucose, and certain amino acids that are necessary for the physiological functioning of the brain (7). Furthermore, it allows the passage of GLUT1, amino acids, and ions via specific transporters (8).

Glucose, the brain’s main energy source, cannot circulate freely across the membrane, so it is transported by the protein GLUT1, the main transporter expressed in endothelial cells of the BBB and by astrocytes (Fig.1). This function occurs independently of insulin and without the consumption of ATP, as it occurs through passive diffusion (9). The BBB ensures a continuous physiological supply of glucose to neurons, which depend almost exclusively on ATP production. Low levels of GLUT1, as occurs in the genetic disorder GLUT1 deficiency syndrome, causes childhood epilepsy, developmental delay, and movement disorders (10). Treatment with a ketogenic diet allows ketone bodies to bypass the need for glucose (11).

Fig. 1. Glucose binds the glucose receptor GLUT1, the main transporter expressed in endothelial cells, to circulate across the blood-brain barrier (BBB), to affect astrocytes and neurons.

The BBB maintains cerebral homeostasis by affecting ionic balance and neurotransmitter levels (12). The BBB is able to block toxins, pathogens, harmful drugs, and other insults, thus protecting the brain (13). Basement membranes are layers rich in collagen and fibronectin that surround the blood vessels (14). This layer provides important structural support to epithelia, acting as an anchor and physical barrier between epithelial cells and the underlying connective tissue (15). Pericytes are cells present in the BBB that support vascularization, helping maintain the integrity of the barrier itself (16). They regulate the proliferation of endothelial cells, participate in angiogenesis, and help to maintain the structural integrity of the BBB, which would otherwise become too permeable (16).

The formation of new blood vessels is called angiogenesis, which usually nourishes tumors, but it is also a critical process for brain development and health. An intact and effective BBB prevents harmful substances from passing from peripheral blood to the brain. This protection is also ensured by phagocytosis, which eliminates debris and dead cells (17). The endothelial cells that make up the BBB form the cerebral capillaries characterized by tight junctions, while astrocytes, which are glial cells, surround the blood vessels, helping regulate BBB function (2).

The BBB transports small lipophilic molecules into the brain, such as oxygen, carbon dioxide, and some drugs, as well as glucose via GLUT1, amino acids, and ions. It also restricts the passage of large hydrophilic molecules, such as most pathogenic microorganisms, toxins, and cells (18). The BBB protects neurons from harmful external influences and maintains cerebral homeostasis, such as ion balance and neurotransmitter levels, by limiting inflammation (19). The BBB can be disrupted by trauma, infection, neuroinflammation, ischemia, or diseases such as multiple sclerosis, AD, and stroke, which can cause neuroinflammation, edema, and neuronal damage (20).

Some microorganisms have developed strategies to cross the BBB and infect the brain, causing meningitis, encephalitis, and other CNS infections (21). Transcellular microorganisms, such as Listeria monocytogenes, Escherichia coli, Streptococcus pneumoniae, and others, directly cross endothelial cells (22). Paracellular microorganisms, such as Neisseria meningitidis, which can release endotoxins that increase permeability, alter tight junctions to pass the endothelial cell barrier (23). In some cases, the BBB is bypassed by the passage of infected immune cells, as occurs with HIV and Mycobacterium tuberculosis (24). Other viruses that can cross the BBB include herpes simplex virus, rhabdoviruses, arboviruses (e.g., West Nile virus), and SARS-CoV-2 (in some cases) (25). Fungi such as Cryptococcus neoformans, protozoa such as Naegleria fowleri, and Toxoplasma gondii can also cross the BBB and damage brain tissue (26).

CONCLUSIONS

The BBB is highly specialized in protecting the CNS by selectively controlling what is able to enter it, and by maintaining homeostasis to create a stable and safe environment. This selectivity is expressed with respect to glucose, the brain’s primary energy source on which neurons depend. Glucose does not passively cross the BBB but is transported via the GLUT1 transporter. The BBB maintains a constant supply of glucose even when peripheral blood glucose levels fluctuate. Neurons are protected by the BBB, which ensures their proper health and function.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

1. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nature Medicine. 2013;19(12):1584-1596. doi:https://doi.org/10.1038/nm.3407
2. Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and Function of the Blood–brain Barrier. Neurobiology of Disease. 2010;37(1):13-25. doi:https://doi.org/10.1016/j.nbd.2009.07.030
3. Rehman IU, Park JS, Choe K, Park HY, Park TJ, Kim MO. Overview of a novel osmotin abolishes abnormal metabolic-associated adiponectin mechanism in Alzheimer’s disease: Peripheral and CNS insights. Ageing Research Reviews. 2024;100:102447. doi:https://doi.org/10.1016/j.arr.2024.102447
4. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature Reviews Neuroscience. 2011;12(12):723-738. doi:https://doi.org/10.1038/nrn3114
5. Braniste V, Al-Asmakh M, Kowal C, et al. The gut microbiota influences blood-brain barrier permeability in mice. Science Translational Medicine. 2014;6(263):263ra158-263ra158. doi:https://doi.org/10.1126/scitranslmed.3009759
6. Wu D, Chen Q, Chen X, et al. The blood–brain barrier: Structure, regulation and drug delivery. Sig Transduct Target Ther. 2023;8(1):217. Doi:https://doi.org/10.1038/s41392-023-01481-w
7. Hou Y, Xie Y, Liu X, Chen Y, Zhou F, Yang B. Oxygen glucose deprivation-pretreated astrocyte-derived exosomes attenuates intracerebral hemorrhage (ICH)-induced BBB disruption through miR-27a-3p /ARHGAP25/Wnt/β-catenin axis. Fluids and Barriers of the CNS. 2024;21(1). doi:https://doi.org/10.1186/s12987-024-00510-2
8. Veys K, Fan Z, Ghobrial M, et al. Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity. Circulation Research. 2020;127(4):466-482. doi:https://doi.org/10.1161/circresaha.119.316463
9. Harry GJ. Microglia during development and aging. Pharmacology & Therapeutics. 2013;139(3):313-326. doi:https://doi.org/10.1016/j.pharmthera.2013.04.013
10. Pervaiz I, Mehta Y, Al‐Ahmad AJ. Glucose Transporter 1 Deficiency Impairs Glucose Metabolism and Barrier Induction in Human Induced Pluripotent Stem Cell‐Derived Astrocytes. Journal of Cellular Physiology. 2025;240(1). doi:https://doi.org/10.1002/jcp.31523
11. Falsaperla R, Sortino V, Vitaliti G, et al. GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review. Neurogenetics. 2024;25(2):69-78. doi:https://doi.org/10.1007/s10048-023-00742-8
12. Guo W, Ji M, Li Y, et al. Iron Ions-Sequestrable and Antioxidative Carbon dot-based Nano-formulation with Nitric Oxide Release for Parkinson’s Disease Treatment. Biomaterials. 2024;309:122622-122622. doi:https://doi.org/10.1016/j.biomaterials.2024.122622
13. Rajagopal N, Irudayanathan FJ, Nangia S. Computational Nanoscopy of Tight Junctions at the Blood–Brain Barrier Interface. International Journal of Molecular Sciences. 2019;20(22):5583. doi:https://doi.org/10.3390/ijms20225583
14. Michalski D, Spielvogel E, Puchta J, et al. Increased Immunosignals of Collagen IV and Fibronectin Indicate Ischemic Consequences for the Neurovascular Matrix Adhesion Zone in Various Animal Models and Human Stroke Tissue. Frontiers in physiology. 2020;11. doi:https://doi.org/10.3389/fphys.2020.575598
15. Wei C, Jiang W, Wang R, et al. Brain endothelial GSDMD activation mediates inflammatory BBB breakdown. Nature. 2024;629(8013):893-900. doi:https://doi.org/10.1038/s41586-024-07314-2
16. Qiu Y, Zhang C, Chen A, et al. Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy? Frontiers in Immunology. 2021;12. doi:https://doi.org/10.3389/fimmu.2021.678744
17. Deepika, Maurya PK. Health Benefits of Quercetin in Age-Related Diseases. Molecules. 2022;27(8):2498. doi:https://doi.org/10.3390/molecules27082498
18. Dobrogowska DH, Vorbrodt AW. Quantitative Immunocytochemical Study of Blood-Brain Barrier Glucose Transporter (GLUT-1) in Four Regions of Mouse Brain. Journal of Histochemistry & Cytochemistry. 1999;47(8):1021-1030. doi:https://doi.org/10.1177/002215549904700806
19. Vatine GD, Barrile R, Workman MJ, et al. Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications. Cell Stem Cell. 2019;24(6):995-1005.e6. doi:https://doi.org/10.1016/j.stem.2019.05.011
20. Zorbaz T, Madrer N, Soreq H. Cholinergic blockade of neuroinflammation: from tissue to RNA regulators. Neuronal Signaling. 2022;6(1). doi:https://doi.org/10.1042/ns20210035
21. Yadav P, Lee YH, Panday H, et al. Implications of Microorganisms in Alzheimer’s Disease. Current Issues in Molecular Biology. 2022;44(10):4584-4615. doi:https://doi.org/10.3390/cimb44100314
22. Cheng Z, Zheng Y, Yang W, et al. Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood–brain barrier. Proceedings of the National Academy of Sciences of the United States of America. 2023;120(39). doi:https://doi.org/10.1073/pnas.2307899120
23. Delbaz A, Chen M, Jen FEC, et al. Neisseria meningitidis Induces Pathology-Associated Cellular and Molecular Changes in Trigeminal Schwann Cells. Infection and Immunity. 2020;88(4). doi:https://doi.org/10.1128/IAI.00955-19
24. Alvarez-Cermen˜o JC, Varela JM, Villar LM, et al. Intrathecal synthesis of soluble class I antigens (sHLA) in patients with HIV infection and tuberculous meningitis. Journal of the Neurological Sciences. 1990;100(1-2):152-154. doi:https://doi.org/10.1016/0022-510x(90)90026-j
25. Feige L, Zaeck LM, Sehl-Ewert J, Finke S, Bourhy H. Innate Immune Signaling and Role of Glial Cells in Herpes Simplex Virus- and Rabies Virus-Induced Encephalitis. Viruses. 2021;13(12):2364. doi:https://doi.org/10.3390/v13122364
26. Carter CJ. Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease. Journal of Alzheimer’s Disease Reports. 2017;1(1):125-157. doi:https://doi.org/10.3233/adr-170017