Blood Brain Barrier Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Transport Systems, and Disease-Specific Alterations

Abstract

The blood-brain barrier (BBB) is a very specialized dynamic interface which maintains homeostasis in the central nervous system through tightly controlled molecular and cellular interchange between the blood and the brain. It is growingly recognized that BBB dysfunction is a rather acute and primary pathogenic factor of neurodegenerative diseases but not the result of neuronal death. This review summarizes existing information about the molecular pathways involved in the disruption of BBB in several of the most common neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. We pay attention to changes of endothelial tight junctions, pericyte degeneration, astrocyte malfunction, neuroinflammation, oxidative stress, and remodeling of the extracellular matrix that all undermine the integrity of barriers. Besides that, we also discuss disease-specific modifications in BBB transport systems including glucose transporters, ATP-binding cascade efflux pumps, receptor-mediated transcytosis routes, and the ion transport and clearance of toxins, which play a pivotal role in nutrient delivery, toxin clearance, and drug permeability. A clear comprehension of these molecular and transport changes in various conditions of neurodegeneration offers insight to the disease progressions and heterogeneity. Lastly, we comment on the early therapeutic interventions and drugs that are now being developed to repair BBB functionality or selectively regulate its transport characteristics with the BBB serving as a source of biomarker and as a potential therapeutic target in neurodegenerative disease.