Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry...

Area of Science:

• Neuroscience
• Cerebrovascular Biology
• Alzheimer's Disease Research

Background:

• The blood-brain barrier (BBB) and neurovascular unit (NVU) regulate brain homeostasis, controlling nutrient supply and waste clearance.
• Dysfunction in the NVU/BBB, linked to altered cerebral blood flow (CBF), is implicated in Alzheimer's disease (AD) pathogenesis, particularly in impaired beta-amyloid (Aβ) clearance.
• The precise role of NVU/BBB dysfunction in the early stages of neurodegeneration remains unclear.

Purpose of the Study:

• To investigate the impact of chronic cerebral hypoperfusion on NVU/BBB function and its role in initiating AD-like pathology.
• To elucidate the molecular mechanisms linking hypoperfusion, BBB integrity, and Aβ deposition.
• To explore potential therapeutic interventions targeting metabolic dysregulation.

Main Methods:

• Induction of mild chronic cerebral hypoperfusion in C57BL/6J mice via permanent right common carotid artery ligation.
• Assessment of NVU/BBB integrity, including ABCB1 protein expression and beta-catenin localization.
• Monitoring of peripherally administered Aβ1-42 deposition and aggregation in the brain.
• Evaluation of the effects of brain reperfusion and glucose administration on molecular markers and Aβ deposition.

Main Results:

• Cerebral hypoperfusion led to NVU dysfunction by decreasing brain capillary ABCB1 expression, primarily through enhanced Glycogen Synthase Kinase 3 beta (GSK3β) activation and reduced beta-catenin nuclear abundance.
• Mild hypoperfusion resulted in early vascular deposition of peripherally applied Aβ1-42 peptides, which later shifted to the parenchyma, forming stable deposits.
• Metabolic deregulation, evidenced by altered glucose metabolism, was observed. Brain reperfusion or high-dose glucose administration reversed GSK3β activation, restored beta-catenin and ABCB1 levels, and prevented early Aβ vascular deposition.

Conclusions:

• Mild chronic cerebral hypoperfusion creates a deregulated brain microenvironment that promotes the entry and aggregation of peripheral Aβ peptides.
• These findings offer novel insights into the early neurodegenerative processes in AD, highlighting metabolic and vascular dysfunction as key initiators.
• Targeting metabolic pathways and restoring BBB integrity may represent promising therapeutic strategies for AD.