The blood-brain barrier (BBB) is cropping up with increasing frequency in discussions of Alzheimer's disease therapy. It is an ever-present concern for researchers hoping to introduce therapies-whether drugs, a vaccine, or stem cells-to the brain via a noninvasive route (see ARF related news story). Moreover, there are indications that the BBB was compromised in the recent clinical Ab immunization trials (see ARF related news story). .
In the June 15 Nature Medicine, researchers led by Kyu-Won Kim of Seoul National University in Korea, reports that a putative tumor suppressor called src-suppressed C-kinase substrate (SSeCKS, produced by the gene known as Akap12) regulates the formation of the BBB during embryonic development, and may play a role in its maintenance. Kim's team of scientists from Korea and the United States found evidence that SSeCKS expression is regulated by oxygen tension in the fine capillaries that are laid down during angiogenesis. As hypoxic regions gradually disappear from the developing brain, the expression of SSeCKS by astrocytes is upregulated, in turn inhibiting the migration of endothelial cells that form capillaries.
In addition, the authors report, SSeCKS promotes the process whereby the capillaries, in concert with astrocytes, form the tight junctions between endothelial cells that characterize the impermeable BBB. SSeCKS appears to effect these changes by downregulating expression of vascular endothelial growth factor (VEGF) through AP-1 reduction, and by upregulating expression of angiopoietin-1 (Ang-1), an astrocyte-derived antipermeability factor.
Previous work has shown that SSeCKS expression is ubiquitous in the adult brain. "[W]e suggest that the constitutive expression of SSeCKS in the adult brain may provide a stabilizing signal for BBB integrity under physiological conditions. A detailed understanding of BBB formation by SSeCKS will be helpful in the development of therapeutics for brain diseases related to BBB disruption," write the authors. Perhaps this knowledge will also be useful for understanding how the BBB changes in diseases such as Alzheimer's, and what role, if any, angiogenesis plays in this process.—Hakon Heimer
- Lee SW, Kim WJ, Choi YK, Song HS, Son MJ, Gelman IH, Kim YJ, Kim KW. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med. 2003 Jul;9(7):900-6. PubMed.