Endothelial BACE1 Impairs Cerebral Small Vessels via Tight Junctions and eNOS

Area of Science:

• Neuroscience
• Vascular Biology
• Biochemistry

Background:

• Cerebral small vessel injury is a hallmark of neurodegenerative diseases like Alzheimer's and hypertension-related conditions.
• Endothelial dysfunction and blood-brain barrier breakdown are key features of these injuries.
• Elevated BACE1 (β-site amyloid precursor protein cleaving enzyme 1) in cerebral vessels suggests its potential role in small vessel damage.

Purpose of the Study:

• To investigate the contribution of vascular BACE1 to cerebrovascular impairments.
• To elucidate the pathological mechanisms underlying BACE1-induced cerebral small vessel injury.

Main Methods:

• Utilized cellular and molecular techniques, mass spectrometry, and immunostaining.
• Employed functional testing in endothelial-specific BACE1 transgenic mice.
• Assessed the impact of BACE1 inhibition on cerebrovascular and cognitive functions.

Main Results:

• BACE1 expression increased 3.71-fold in cerebral microvessels of hypertensive patients.
• Identified occludin as a novel substrate for endothelial BACE1, leading to tight junction disruption.
• Demonstrated that BACE1 inhibition ameliorates endothelial dysfunction and cognitive deficits in vivo.

Conclusions:

• Established a direct link between endothelial BACE1 and cerebral small vessel damage.
• Proposed that elevated endothelial BACE1 is a novel pathogenic mechanism for cerebral small vessel disease.
• Highlighted BACE1 as a potential therapeutic target for cerebrovascular disorders.