Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

Area of Science:

• Neuroscience
• Vascular Biology
• Alzheimer's Disease Research

Background:

• Alzheimer's disease (AD) brains show increased angiogenic markers, yet reduced cerebral microvasculature near amyloid-beta (Aß) plaques.
• The paradoxical vascular changes in AD suggest complex dysregulation of blood vessel formation and maintenance.

Purpose of the Study:

• To investigate the mechanisms behind paradoxical vascular changes in Alzheimer's disease.
• To explore the role of non-productive angiogenesis (NPA) and microglial activity in AD-related vascular pathology.

Main Methods:

• Analysis of AD mouse models and human AD brain samples.
• Assessment of endothelial cell markers, NOTCH pathway activity, and microglial phagocytosis.
• Investigating the impact of presenilin deficiency on vascular phenotype.

Main Results:

• Angiogenesis initiates near Aß plaques, but endothelial cells exhibit a non-productive angiogenesis (NPA) signature.
• Reduced NOTCH activity and vascular anomalies are observed around Aß plaques.
• Endothelial loss of presenilin induces NPA and vascular defects independently of Aß pathology.
• Aß plaque-associated NPA leads to local blood vessel disassembly and vascular scarring, with microglial phagocytosis contributing to endothelial cell loss.

Conclusions:

• Non-productive angiogenesis (NPA) and microglial phagocytosis are key drivers of local blood vessel disassembly in Alzheimer's disease.
• Presenilin deficiency contributes to vascular pathology in AD, highlighting the vascular component of this neurodegenerative disease.