Microglial AT1R Conditional Knockout Ameliorates Hypoperfusive Cognitive Impairment by Reducing Microglial...

Area of Science:

• Neuroscience
• Pharmacology
• Pathology

Background:

• Chronic cerebral hypoperfusion (CCH) is a significant cause of vascular cognitive impairment and dementia.
• The precise role of the angiotensin II type I receptor (AT1R) in the central nervous system during CCH remains incompletely understood.

Purpose of the Study:

• To investigate the specific function of microglial AT1R in the context of CCH.
• To evaluate the therapeutic potential of AT1R antagonism in mitigating CCH-induced cognitive deficits.

Main Methods:

• Utilized a bilateral carotid artery stenosis (BCAS) model to induce CCH.
• Employed conditional knockout of microglial AT1R and pharmacological blockade with candesartan.
• Assessed cognitive function, microglial activation, inflammatory responses, and cerebral blood flow (CBF).

Main Results:

• CCH significantly increased AT1R expression in the hippocampus and hippocampal microglia.
• Conditional knockout of microglial AT1R and candesartan treatment ameliorated cognitive impairment.
• These interventions reduced neuroinflammation and microglial activation, with restored CBF but no significant neuronal loss observed at 28 days post-BCAS.
• Identified hub genes (Ctss, Fcer1g, Tyrobp) associated with CCH.

Conclusions:

• Microglial AT1R plays a critical role in exacerbating CCH-induced cognitive impairment by modulating neuroinflammation.
• AT1R antagonism presents a promising therapeutic strategy for managing cognitive decline associated with CCH and vascular dementia.