Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

Abstract

The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented.

Figure 1. The blood-brain barrier

Brain capillaries are a key site of the blood–brain barrier (BBB). The capillary cross-section (large inset) shows a tightly sealed endothelium, which shares a common basement membrane with pericytes, and astrocyte end-feet wrapping around the capillary wall. The arterial cross section (small inset) shows perivascular flow of interstitial fluid (ISF) through the arterial wall in the opposite direction to blood flow; paravascular flow might also occur in the same direction as blood flow. CSF is produced by the choroid plexus and flows from brain ventricles into subarachnoid spaces, draining into the meningeal lymphatic system and/or venous blood through the arachnoid villi. ISF can exchange with CSF in the ventricles (not shown) and subarachnoid spaces. ECS, extracellular space.

Figure 2. Key transport properties of the capillary endothelium

a | Tight junctions (TJ), adherens junctions (AJ), and junctional adhesion molecules (JAMs) prevent free paracellular exchanges of solutes. Lack of pinocytosis and bulk flow transcytosis contributes to the endothelial barrier function. b | O₂ and CO₂ cross the blood–brain barrier (BBB) by simple diffusion, as do small lipophilic molecules (such as ethanol). c | Solute carrier-mediated transport (CMT) of metabolites, nutrients, vitamins, nucleotides and other substrates, according to substrate specificity and concentration gradient. d | Receptor-mediated transcytosis (RMT) of peptides and proteins. e | NLS1 (sodium-dependent lysophosphatidylcholine symporter 1) transports ω3 essential fatty acids into the brain. f | Ion concentrations are regulated by the abluminal sodium pump (Na⁺,K⁺ATPase), the luminal sodium-hydrogen exchanger, chloride-bicarbonate exchanger, luminal sodium-potassium-chloride cotransporter, and sodium-calcium exchanger. Water is transported via aquaporin (AQP) receptors: AQP1 on endothelial cells and AQP4 on astrocytic end-feet. g | ATP-binding cassette (ABC) active efflux transporters limit entry of drugs, xenobiotics, and drug conjugates. h | Neurotoxic substances are cleared by phosphatidylinositol binding clathrin assembly protein (PICALM)-mediated transcytosis and LDL receptor-related protein-1 (LRP1), which removes toxic amyloid-β (Aβ) species linked to Alzheimer disease (AD). Excitatory acidic amino acid CMT transporters EAAT1 and EAAT2 clear neurotoxic glutamate and aspartate. However, receptor for advanced glycation end products (RAGE) is upregulated in AD and mediates re-entry of circulating Aβ, which increases brain Aβ levels. i | Solutes diffusing across brain extracellular spaces (ECS) (dotted arrows) are cleared via transvascular transport (c–e, g–i) and by perivascular ISF flow within the arterial wall (solid arrow), in the reverse direction of the blood flow, eventually reaching the CSF-filled subarachnoid space and draining into meningeal lymphatic vessels and cervical lymph nodes.

Figure 3. Blood-brain barrier (BBB) breakdown promotes neurodegeneration

BBB breakdown is characterized by pericyte and endothelial degeneration, with loss of tight and adherens junctions and increased bulk flow transcytosis. BBB breakdown leads to the entry of microbial pathogens, accumulation of neurotoxic material faulty BBB transport, red blood cell extravasation and the release of neurotoxic free iron (Fe²⁺), which generates reactive oxygen species and oxidative stress. Inflammatory and immune responses lead to the generation of autoantibodies. CMT, solute carrier-mediated transport; ECS, extracellular spaces, L-DOPA, L-3,4-dihydroxyphenylalanine; RMT, receptor-mediated transcytosis.

Figure 4. Blood-brain barrier (BBB) dysfunction – implications for drug delivery

In a healthy BBB (left), strategies to breach the barrier and deliver neuropharmaceuticals to brain rely on carrier-mediated transporters (CMT), receptor-mediated transporters (RMT), nanoparticles, and/or transient opening of BBB as for example by focused ultrasound. Under pathological conditions (right), the disrupted BBB leads to accumulation of blood-derived debris and cells into enlarged perivascular spaces. This blocks normal distribution of molecules throughout the CNS by concentration gradient-driven diffusion across brain extracellular spaces (ECS) and interrupts regionally formation of interstitial fluid (ISF) and ISF flow preventing the therapeutic antibodies, proteins, peptides, gene medicine and other drugs to efficiently reach their neuronal targets. See main text for details.