Ilana Spokoyny, MD
Accumulating senescent cells in tissues is known to contribute to age-related systemic organ dysfunction. The authors investigated whether a similar process happens in the cerebral vasculature, leading to compromised blood–brain barrier and potentially contributing to neurodegenerative and cerebrovascular diseases. The blood–brain barrier (BBB) is kept intact by endothelial cells (ECs) forming tight junctions, and these ECs are covered by pericytes, astrocyte end-feet, and the capillary basement membrane. BBB integrity is compromised by aging, but the exact process by which this occurs is still unknown. We know that senescent cells limit the regeneration potential of tissues and that there are more senescent vascular smooth muscle cells and endothelial cells found in aged peripheral vessels and atherosclerotic lesions, but the effects of increased senescent cells on the BBB have not been well studied.
The authors used both an in vitro model made of endothelial cells, pericytes, and astrocytes; and an in vivo model in mice with accelerated aging phenotypes. In the in vitro model using senescent ECs and PCs, tight junction structure and barrier integrity were significantly impaired compared with the model using young ECs and PCs. The authors also determined that the reduced BBB integrity is due to altered TJ structure and distribution in the EC layer, rather than with decreased TJ protein expression.
The in vivo model also demonstrated this, with an exacerbation of senescence and compromised BBB integrity. Specifically, the coverage of cortical microvessels by tight junction proteins was impaired, but the coverage of microvessels by astrocytuc end-feet was not altered.
Limitations are noted, especially in the in vitro model, due to needing to keep the three cell types in different media (ECs in one, PCs and astrocytes in another); so the possibility exists that if they were mixed we would see different effects. This is compensated by the in vivo model, however. Overall, this is an important study demonstrating a critical link and setting the foundation for future diagnostic and therapeutic advances in cerebrovascular and neurodegenerative disorders.