In contrast to other vascular endothelial cells found in the peripheral organs, specialised BMECs lack fenestrations (with only ~ 4 nm wide extracellular gaps limited by TJs being present between BMECs as compared to 50 nm wide intracellular gaps in peripheral endothelium). At the molecular level, those junctional complexes are organised into sophisticated structures involving transmembrane proteins (such as claudins, occludins and junctional adhesion molecules (JAMs)) and numerous auxiliary proteins (as zonula occludens proteins, ZO-1, ZO-2 and ZO-3) that link adjacent BMECs and limit the para-cellular permeability of the BBB. The BBB is primarily formed by the specialised brain microvascular endothelial cells (BMECs) closely connected through tight junctions (TJs), adherent junctions (AJs), and gap junctions (GJs). Although essential for brain functioning, the BBB limits the ability of therapeutic agents to penetrate into the CNS, representing a major challenge in the treatment of neurodegenerative disorders. By separating the circulating blood from the brain, it protects the central nervous system (CNS) from harmful molecules and pathogens, while at the same time maintaining tightly regulated brain homeostasis. The blood-brain barrier (BBB) formed in all cerebral capillaries is a dynamic multicellular interface that controls the exchange of molecules between the blood and the brain parenchyma. The Blood-brain Barrier as a Major Obstacle to Drug Delivery in Neurodegenerative Diseases With safe and effective application, this innovative FUS+MB technology may open new avenues for therapeutic interventions in neurodegenerative diseases leading to improved clinical outcomes for patients. This review summarizes key features of the BBB that contribute to limited drug delivery, recapitulates recent advances in the FUS+MB mediated human BBB opening in vivo and in vitro in the context of neurodegenerative disorders, and highlights potential strategies for fast-track translation of the FUS+MB to improve bioavailability of drugs to the human brain. Simultaneously, rapid progress in the human induced pluripotent stem cell (hiPSC) modeling technology allowed for development of novel Alzheimer’s disease patient-derived BBB in vitro model that reacts to FUS+MB with BBB opening and can be used to answer fundamental questions of human BBB responses to FUS+MB in health and disease. As a step towards translation, small cohort clinical studies were performed demonstrating safe BBB opening in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) patients following FUS+MB, however improved drug delivery has not yet been achieved in human. Recent preclinical evidence demonstrates that following application of focused ultrasound with microbubbles (FUS+MB), the BBB becomes reversibly accessible to compounds that normally are brain-impermeable, suggesting FUS+MB as a promising new platform for delivery of therapeutic agents into the central nervous system. The blood-brain barrier (BBB) has a major protective function in preventing the entry of harmful molecules into the brain, but is simultaneously limiting the delivery of drugs, restricting their potential clinical application in neurodegenerative diseases.
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