The blood brain barrier: Insights from development and ageing

Abstract

The blood brain barrier is a necessity for cerebral homeostasis and response to environmental insult, thus loss in functionality with age creates opportunities for disease to arise in the aged brain. Understanding how the barrier is developed and maintained throughout the earlier years of adult life can identify key processes that may have beneficial applications in the restoration of the aged brain. With an unprecedented increasing global aged population, the prevention and treatment of age-associated disorders has become a rising healthcare priority demanding novel approaches for the development of therapeutic strategies. The aging cardiovascular system has long been recognised to be a major factor in age-associated diseases such as stroke, atherosclerosis and cardiac arrest. Changes in the highly specialised cerebral vasculature may similarly drive neurodegenerative and neuropsychiatric disease.

Keywords: ageing; biology of endothelial barriers; blood brain barrier; dementia; psychiatric illness; tight junctions.

Figure 1.

The Healthy Neurovascular Unit and Endothelial Tight junction. The normal/healthy tight junction is located at the apical periphery of two contacting endothelial cells or indeed at the point of contact of one endothelial encompassing the entire lumen of a vessel. The most enriched tight junction components in a normal/healthy brain endothelial cell tight junction are claudins-3, −5 and −12. Additionally, occludin and junctional adhesion molecule (JAM) are highly enriched at the blood brain barrier (BBB) compared to peripheral endothelial cells. Located below the tight junction is the adherens junction, comprising cadherins, catenins and nectin amongst others.

Figure 2.

The Aged Neurovascular Unit and Aberrant Trans-Endothelial Transport. Tight junction breakdown is evident across a plethora of age associated neuropathies. Breakdown of the paracellular pathway can lead to extravasation of blood-borne material such as IgG, fibrinogen and autoantibodies into the delicate neural tissues. Additionally, pericyte loss and transcellular permeability can increase, with differential expression of basal lamina components matrix metalloproteinase-9 (MMP9), Tissue inhibitor of matrix metalloproteinase-2 (TIMP2) and collagen. Astrocyte components aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP), pericyte components low density lipoprotein receptor-related protein-1 (LRP1) and pro-inflammatory nuclear factor kappa-B (Nf-kB). Endothelial molecules zonula-occludens-1 (ZO-1), occludin, P-glycoprotein (PgP), Vascular cell adhesion protein-1 (VCAM), receptor for advanced glycation end products (RAGE) and tumour necrosis factor-alpha (TNF-alpha).