Angiopoietin-2 (ANGPT2) is not to be mistaken for angiopoietin-like protein 2 (ANGPTL2), but both appear problematic in similar contexts. Angiopoietins are in the vascular growth factor family, and angiopoietin-like proteins are, as the name suggests, somewhat similar. They are involved in the inflammatory response to damage that resolves into regeneration in the vascular system. Unfortunately, as in the rest of the body, the mechanisms involved in this response to damage run awry with advancing age and contribute to dysfunction rather than helping to address it. So, to pick a few examples, the presence of ANGPTL2 is a marker of cellular senescence and contributes to inflammatory heart disease. Meanwhile, ANGPT2 is known to be involved in the maladaptive reaction to ischemic injuries such as a heart attack, inducing excessive inflammation and further loss of function.
The vasculature extends into the brain, of course, and the aging of the cardiovascular system is known to influence the aging of the brain, an energy-hungry organ that operates at the edge of maximum metabolic capacity at the best of times. The brain is also a distinct microenvironment from the rest of the body; where blood vessels pass through the brain, they are wrapped by the structures of the blood-brain barrier. The blood-brain barrier restricts the passage of cells and molecules to and from the brain. Unfortunately, vascular dysfunction also implies blood-brain barrier dysfunction, and thus leakage of unwanted molecules and cells into the brain where they can induce damage and inflammation. In today's open access paper, researchers extend what is known of the issues induced by ANGPT2 expression in the aging vasculature to include harmful effects on the blood-brain barrier, and thus a contribution to the onset and progression of neurodegenerative conditions.
Alzheimer's disease (AD) is a fatal neurodegenerative disorder. Emerging evidence highlights neuroinflammation as a crucial factor in AD pathogenesis and progression, with the disruption of the blood-brain barrier (BBB) significantly contributing to this process. The BBB constitutes a pivotal aspect of the neurovascular unit (NVU), a distinct structural and functional complex formed by endothelial cells, pericytes, and astrocytes within the central nervous system (CNS), specialized for tightly regulated interactions among vascular cells, glial cells, and neurons. NVU cell interactions are crucial for maintaining brain homeostasis, modulating immune responses, and facilitating neural communication. BBB disruption is closely linked to NVU dysfunction, which contributes to neuroinflammation and cognitive impairment in many neurological disorders, including AD.
In this study, we identified ANGPT2 as a key vascular determinant upregulated in human AD brains, as demonstrated by transcriptomic analyses and validated in postmortem tissues. To investigate its role in AD pathogenesis, we utilized the 5xFAD transgenic mouse model, which harbors five familial AD mutations that accelerate β-amyloid deposition.
Endothelial-specific deletion of ANGPT2 reduced β-amyloid accumulation, whereas ANGPT2 overexpression via adeno-associated viral (AAV) delivery exacerbated β-amyloid deposition. Mechanistically, ANGPT2 inhibition of TIE2 signaling compromised BBB integrity and amplified microglial activation and neuroinflammation, ultimately exacerbating cognitive dysfunction. Furthermore, single-nucleus RNA sequencing (snRNA-seq) from AD mice revealed ANGPT2-driven transcriptional changes consistent with microglial dysfunction and neuronal impairment. Collectively, these findings demonstrate that ANGPT2 promotes BBB dysfunction and neuroinflammation, thereby serving as a critical driver of AD pathology and progression.
View the full article at FightAging
