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Liposome nanoparticles functionalized with TfR ligands represent a promising drug delivery approach tested currently in preclinical trials in brain cancer, stroke, and Parkinson’s, Alzheimer’s, and Huntington’s disease, but the levels of nanoparticle transport into the brain need to improve to meet dosage requirements and reach clinical significance 12, 13. In comparison, nanoparticle drug carriers are versatile delivery vehicles that can encapsulate large payloads of xenobiotics with a wide range of biophysical characteristics, offering diverse and unique therapeutic opportunities 9, 10, 11. Neuroprotective compounds show enhanced brain delivery when coupled to TfR ligands, e.g., antibody fragments 14, 15, but require chemical conjugation to the targeting moiety. The flagship ferrying receptor on BECs used for that purpose is the transferrin receptor (TfR) 8, 12, 13. Consequently, the BBB precludes more than 99% of neuroprotective compounds from reaching the brain, rendering central nervous system (CNS) disorders resistant to most conventional therapies 3, 7, 8.ĭrug delivery systems that aim to adapt receptor-mediated transcytosis (RMT) to shuttle therapeutic cargo across the BBB are currently at the forefront of modern therapeutic approaches against brain diseases 9, 10, 11. Macromolecules, e.g., proteins, can enter the brain by vesicular transport, i.e., transcytosis, but this route is highly selective and actively suppressed by recently identified homeostatic mechanisms 5, 6. Most of them, however, including therapeutics, show negligible brain uptake due to rapid outward transport by efflux pumps to the bloodstream 3, 4.
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Diffusion of molecules across BECs is possible but restricted to low-molecular-weight hydrophobic compounds. The paracellular entry of molecules from the blood to the brain is barred by junctional complexes between adjoining brain endothelial cells (BEC) 2. The blood-brain barrier (BBB) is impermeable to most blood-borne substances, protecting the fragile brain environment from potentially harmful insults 1. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries. We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo. However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Thus, through regulation of growth factors and reduction of peripheral and central risk factors, exercise ensures successful brain function.Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). A common mechanism underlying the central and peripheral effects of exercise might be related to inflammation, which can impair growth factor signaling both systemically and in the brain. In addition, exercise reduces peripheral risk factors such as diabetes, hypertension and cardiovascular disease, which converge to cause brain dysfunction and neurodegeneration.
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A key mechanism mediating these broad benefits of exercise on the brain is induction of central and peripheral growth factors and growth factor cascades, which instruct downstream structural and functional change. Such exercise-induced structural and functional change has been documented in various brain regions but has been best-studied in the hippocampus - the focus of this review. Exercise increases synaptic plasticity by directly affecting synaptic structure and potentiating synaptic strength, and by strengthening the underlying systems that support plasticity including neurogenesis, metabolism and vascular function. The benefits of exercise have been best defined for learning and memory, protection from neurodegeneration and alleviation of depression, particularly in elderly populations. Human and other animal studies demonstrate that exercise targets many aspects of brain function and has broad effects on overall brain health.