Healthy aging and the blood-brain barrier

Abstract

The blood-brain barrier (BBB) protects the central nervous system (CNS) from unregulated exposure to the blood and its contents. The BBB also controls the blood-to-brain and brain-to-blood permeation of many substances, resulting in nourishment of the CNS, its homeostatic regulation and communication between the CNS and peripheral tissues. The cells forming the BBB communicate with cells of the brain and in the periphery. This highly regulated interface changes with healthy aging. Here, we review those changes, starting with morphology and disruption. Transporter changes include those for amyloid beta peptide, glucose and drugs. Brain fluid dynamics, pericyte health and basement membrane and glycocalyx compositions are all altered with healthy aging. Carrying the ApoE4 allele leads to an acceleration of most of the BBB's age-related changes. We discuss how alterations in the BBB that occur with healthy aging reflect adaptation to the postreproductive phase of life and may affect vulnerability to age-associated diseases.

Fig. 1 |. Properties of the peripheral endothelial cell versus the vBBB or brain endothelial cell.

The upper portion of the figure shows the major characteristics of the vBBB: absence of macropinocytosis and fenestrae, tight junctions limiting paracellular diffusion, polarized cell membrane with different proteins in the luminal versus abluminal membrane leaflets, unidirectional and bidirectional saturable and nonsaturable (transcellular diffusion) mechanisms of BBB penetration, a glycocalyx and a BM. The lower portion of the figure shows the morphological basis for leakage of peripheral capillaries: paracellular diffusion, macropinocytosis and the presence of window-like fenestrae. Some peripheral capillaries possess tight junctions but are leakier than the BBB is.

Fig. 2 |. Movement of brain fluids via diffusion and convection.

Diffusion is unaltered with normal aging, whereas many aspects of convection are. a, Diffusion, mainly driven by Brownian motion, is characterized by dispersion that is symmetrical and faster for substances with lower molecular weights. b–d, Convection is driven by several forces that differ among the regions. b, CSF is produced by the choroid plexus located in the ventricular system, is reabsorbed at the arachnoid villi and drains to the nasal lymphatics. c, In the perivascular space, fluid is mixed or driven towards the venule end of the capillary bed and into the brain interstitial-fluid space by arteriole pulsations and production of free water by astrocytic AQP4 channels; production of free water increases oncotic pressure. Interstitial fluid moves through tortuous channels between the various cells that form brain parenchyma. Metabolic free water increases oncotic pressure in the interstitial-fluid space, driving fluid towards CSF compartments. d, CSF and interstitial fluid can enter spaces around blood vessels that penetrate into brain (Virchow-Robin spaces). Interstitial fluid entering a Virchow–Robin space can mix with CSF, and pulsations aid in movement and mixing. CSF entering this space may be able to penetrate deep into brain parenchyma (see question mark and dashed arrow).

Fig. 3|. Impact of ApoE4 on the vBBB.

ApoE4 is associated with an acceleration of many of the age-associated changes that occur at vBBB, both in humans and rodent models. a–c, ApoE4 can lead to structural (a), functional (b) and NVU interaction (c) changes. a, Structural changes at the vBBB include a disruption of the vBBB to various vascular substrates with an increase in paracellular transport^,–,,,, possibly associated with altered tight junction protein regulation (shown in b), such as changes in claudin and occludin In addition, there are changes in BM production, with decreased levels of col IV leading to a thinner BM^,, b, Functional changes at the vBBB include transporter dysfunctions such as changes in LRP-1 transporter expression and activity^, due to shedding of this membrane receptor; increased membrane receptor expression of RAGE; reduced amyloid β efflux; and reduced transport of various vascular substrates, including DHA, glucose and diazepam. There are also alterations in the ability of vascular proteins to bind to brain endothelial cells due to ApoE4, such as decreased binding of insulin. c, Changes in the NVU include pericyte loss and astrocyte inflammation, which could also contribute to vBBB disruption and other BBB dysfunctions. The loss of pericytes is correlated with an increase in CSF levels of a pericyte receptor, PDGFRβ and cyclophilin A (CypA)^,. There are also decreases in cerebral blood flow^, and in vascular density. However, there is no change in vascular space due to ApoE4 (refs. ^,). These data suggest clear evidence for the detrimental effects of ApoE4 on the vBBB with aging.