Age‐associated changes in the blood‐brain barrier: comparative studies in human and mouse
The mechanisms underlying central nervous system (CNS) dysfunction and cognitive deterioration during ageing are complex. It is likely, however, that blood–brain barrier (BBB) dysfunction has a contributory role in the ageing process. The BBB is formed by a continuous layer of cerebral endothelial cells (CECs) held together by tight junctions, which limit paracellular and intramembranous diffusion. This restricts penetration of molecules into the CNS and provides high electrical resistance 1. The ‘sealing’ feature of the tight junctions is due to the unique expression of specific transmembrane proteins, including occludin and junction adhesion molecules (JAMs) 2. Scaffolding proteins, such as zonula occludens‐1 (ZO‐1), link the tight junction complex to the cytoskeleton 4. As a result the molecular traffic of endogenous substances, necessary to maintain CNS homeostasis, occurs mainly by transcellular means. Transport of small molecules, such as glucose and amino acids, requires the expression of specific transporters, whereas larger molecules, such as peptides, cross the BBB by transcytosis. Other transporters specific to CECs, such as P‐glycoprotein (also known as multidrug resistance protein 1 or ATP‐binding cassette subfamily B member 1), are specialized for efflux of a wide range of substrates and contribute to removal of harmful substances from within the CNS 6. The phenotype of CECs is under inductive influence of perivascular pericytes and the end‐feet of astrocytes. Together, these cells form a functional cellular complex termed the ‘neurovascular unit’ (NVU), which provides a coordinated response to maintain CNS homeostasis and function 6.
Leakage of the BBB, associated with changes in the expression of tight junction proteins, has been found in various acute and chronic neurological disorders 7. However, to date, studies investigating the effect of normal, physiological ageing on the integrity of the BBB are conflicting, with some studies concluding the BBB remains intact 12, while others show evidence of increased permeability 17. A systematic review suggests that BBB breakdown may be common in normal human ageing as evidenced by increased cerebrospinal fluid/plasma albumin ratios and brain imaging studies 20. Indeed, our studies in an ageing population‐representative neuropathology cohort show that BBB leakage is a common feature of the cerebral cortex 21 and white matter in the ageing human brain 22, but these studies were confined to the elderly population (>65 years).
To further investigate the effects of ageing on NVU integrity through adult life, we determined BBB permeability in cohorts of mice and an ageing human autopsy cohort, in addition to microvascular density, glial pathology and vascular pathology in the human cohort. Previous studies have shown leakage of serum proteins, such as albumin, fibrinogen and IgG, to be robust markers of impaired BBB function 23, therefore we used albumin‐binding dyes and immunohistochemistry to visualize leakage in mice and human aged tissues respectively. Our findings provide evidence of an age‐associated decline in BBB function which may contribute to the vulnerability of the aged CNS to neurodegenerative disease.