Blood brain barrier (BBB) breakdown is not only a consequence of but also contributes to many neurological disorders, including stroke and Alzheimer's disease. How the basement membrane (BM) contributes to the normal functioning of the BBB remains elusive. Here we use conditional knockout mice and an acute adenovirus-mediated knockdown model to show that lack of astrocytic laminin, a brain-specific BM component, induces BBB breakdown. Using functional blocking antibody and RNAi, we further demonstrate that astrocytic laminin, by binding to integrin α2 receptor, prevents pericyte differentiation from the BBB-stabilizing resting stage to the BBB-disrupting contractile stage, and thus maintains the integrity of BBB. Additionally, loss of astrocytic laminin decreases aquaporin-4 (AQP4) and tight junction protein expression. Altogether, we report a critical role for astrocytic laminin in BBB regulation and pericyte differentiation. These results indicate that astrocytic laminin maintains the integrity of BBB through, at least in part, regulation of pericyte differentiation.
Bibliographical noteFunding Information:
We thank Dr Arturo Alvaraz-Buylla for adenoviruses expressing Cre under GFAP promoter (Ad-pGFAP-Cre), Dr Jonathan Jones for the laminin a4 blocking antibody, Lee Cohen-Gould (Weill Cornell Medical School) and Dr Kunihiro Uryu (The Rockefeller University) for technical support and assistance with electron microscopy. We also thank the lab members of S.S. for scientific support and suggestions. This work was supported by NIH grant NS050537 to S.S., and Merck Postdoctoral Fellowship and BD Stem Cell Grant to Y.Y. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
© 2014 Macmillan Publishers Limited.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't