Cell-Autonomous and Non-Cell-Autonomous Effects of Claudin-5 Loss in the Blood-Brain Barrier

• DOI: 10.2139/ssrn.4524444
• Publication Date: 2023-08-01T14:47:00Z
• Authors: Elisa Vázquez Lié...; Giuseppe Mocci; Bàrbara Laviña; Avril Reddy; Claire O’Connor; Natalie Hudson; Ioannis Nikoloudis; Weihan Li; Konstantin Gaengel; Michael Vanlandew...; Matthew Campbell; Christer Betsholtz; Maarja Andalouss...
• Keywords: Claudin; Blood cell

Claudin-5 (CLDN5) is an endothelial tight junction protein essential for the integrity of developing blood-brain barrier (BBB). Several brain diseases in humans and mice show abnormal CLDN5 expression, transient downregulation Cldn5 at BBB has been proposed as a strategy drug delivery to brain. To study consequences loss adult brain, we induced knockout mice. This resulted mosaic deletion, causing increased permeability from 7 days post induction lethality 11 induction. Single-cell RNA sequencing cells revealed profound differences hundreds transcripts Cldn5iECKO These transcriptomic alterations were almost identical with or without loss, demonstrating non-cell-autonomous reactions dysfunction. Activation microglia astrocytes implicated rapidly ensuing involvement multiple cell types these reactions. Our demonstrates critical role maintaining provides molecular insight into risks associated inhibition.