Angiopoietin-2 aggravates Alzheimer’s disease by promoting BBB breakdown and neuroinflammation.

However, the mechanisms underlying BBB dysfunction and neuroinflammation in AD remain unclear. Angiopoietin-2 (ANGPT2), a ligand for the TIE2 receptor, is known to destabilize blood vessels and compromise vascular integrity under inflammatory conditions.

To investigate the role of ANGPT2 in AD pathology, we overexpressed ANGPT2 specifically in brain endothelial cells using an adeno-associated virus (AAV) system in 5xFAD transgenic mice. Single-nucleus RNA sequencing (snRNA-seq) revealed distinct transcriptional changes associated with ANGPT2 overexpression, pointing to multiple pathways through which ANGPT2 may exacerbate AD progression. These findings identify ANGPT2 as a key driver of BBB dysfunction and neuroinflammation in AD, highlighting it as a potential therapeutic target for mitigating disease progression.