The blood-brain barrier in aging and neurodegeneration

Abstract

The blood-brain barrier (BBB) is vital for maintaining brain homeostasis by enabling an exquisite control of exchange of compounds between the blood and the brain parenchyma. Moreover, the BBB prevents unwanted toxins and pathogens from entering the brain. This barrier, however, breaks down with age and further disruption is a hallmark of many age-related disorders. Several drugs have been explored, thus far, to protect or restore BBB function. With the recent connection between the BBB and gut microbiota, microbial-derived metabolites have been explored for their capabilities to protect and restore BBB physiology. This review, will focus on the vital components that make up the BBB, dissect levels of disruption of the barrier, and discuss current drugs and therapeutics that maintain barrier integrity and the recent discoveries of effects microbial-derived metabolites have on BBB physiology.

Fig. 1. Endothelial cell tight junctions and adherens junction proteins.

The tight junction proteins include claudin-5, occludin, and zonula occludins (ZO-1,2,3). Claudin-5 and occludin are both transmembreane proteins while the zonula occludens are intracellular proteins. The adherens junctions include transcellular components, JAMs, ESAM, PECAM-1, and Ve-cadeherin. The cytoplasmic catenins form a complex with Ve-cadeherin. Actin cytoskeleton helps to anchor the junctional proteins in endothelial cells.

Fig. 2. Transport mechanisms across the blood-brain barrier.

A Passive diffusion across endothelial cells by a limited number of small molecules (blue). B Paracellular transport of limited water-soluble agents (pink) between endothelial cells, through tight junction proteins. C Active efflux transporters (yellow) mostly eliminate drugs and substanes from the brain include many ATP binding cassette (ABC) transporters (purple) which are P-glycoprotein (Pgp), multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP). D Carrier-mediated transport can be in either direction depending on the transporter and can be clatherin-dependent endocytosis. Major transporters include the glucose carrier (GLUT1), the L-type amino acid transporter 1 and 2 (LAT1/2), cationic amino acid transporter 1 and 3 (CAT1/3), the monocarboxylic acid carrier (MCT1/8), the organic anion transporting polypeptide 1c1 (OATP1C1), the fatty acid transport protein 1 and 4 (FATP1/4), the sodium-independent concentrative nucleoside transporter-2 (CNT2), the organic anion transporter 3 (OAT3), organic anion transporter poypeptide 1a4 and 2b1 (OATP1A4 and OATP2B1), and the organic cation transporter 2 (OCTN2). E Receptor-mediated transport relies on the interaction between ligands (green) and receptors to transport larger molecules through the cells. These receptors include the transferrin receptor (TfR), insulin receptor (IR), leptin receptor (LEP-R), lipoprotein receptor 1 and 2 (LRP1/2), and the receptor for advanced glycation end products (RAGE). F Absorptive-mediated transport is caveolin-mediated endocytosis and relies on the interaction between the ligand (orange) and the glycocalyx on the endothelial cells. G Ion transporters (turquoise) regulate the ions between the barrier and includes sodium pumps, calcium transporters, and potassium channels.

Fig. 3. Schematic representation of the blood-brain barrier (BBB) in a healthy state and during BBB breakdown.

A Healthy, intact BBB structure and surrounding cells and key components. Endothelial cells form the main physical barrier lining the blood vessels in the brain with tight junction proteins between them. Leukocytes are in constant circulation. Endothelial cells are encompassed by the basement membrane which also encompasses pericytes which are in close contact to the endothelial cells. Astrocytic endfeet interact closely with the endothelial cells and pericytes and help maintain BBB integrity. Inactivated microglia and functional neurons are present in a healthy neurovascular unit. B During BBB breakdown its integrity can become compromised at various levels. Disruption characteristics of the BBB include endothelial cell alterations such as loss of tight junction proteins, endothelial cell shrinkage, changes in molecular transport at the paracellular level, and transcellular level in some cases, and increased leukocyte infiltration. In some disruption models pericyte dysfunction or loss is apparent as well as astrocyte changes such as swollen or detached endfeet. Microglia can also become activated and neurons may experience demyelination or become damaged.

Fig. 4. Models for studying the blood-brain barrier in health and disease with the respective disruption methods simulating disease and readouts.

In vitro, in vivo, and clinical models have all been used to study blood-brain barrier (BBB) integrity in both health and disease models. Depending on the model of interest, different methods are used to mimic BBB loss of integrity. The assays available to observe and quantify are also different depending on the model of interest. These models, disruption methods, and readouts are highlighted here.

Fig. 5. Proposed summary of the relationship between the gut microbiome and the blood-brain barrier.

A (i) Factors such as the environment, age, circadian rhythm, medication/drugs, exercise, infection, diet and stress can affect the composition and landscape of the gut microbiota. (ii) the gut microbiota and colonized bacteria produce metabolites. These metabolites produced alter with regards to relative concentrations and molecules with changes in microbiota. (iii) gut-derived microbial metabolites cross the gut lumen whether as direct molecules or in derived forms and enter circulation. (iv) once in circulation, the microbial-derived metabolites can interact with the BBB. B In the absence of a gut microbiota (germ-free animals) or where there are compositional alterations in the gut microbiota, microbial metabolites are not produced or are differentially produced that can enter systemic circulation and the lack or increase in microbial-derived metabolites is associated with BBB dysfunction.