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Microglial AT1R Conditional Knockout Ameliorates Hypoperfusive Cognitive Impairment by Reducing Microglial

Deyue Li1, Qiao Zhang2, Xia Yang3

  • 1Department of Pharmacy, The Second Affiliated (Xinqiao) Hospital, The Army (Third Military) Medical University, Chongqing, China.

Neuroscience
|March 14, 2024
PubMed

Insights

Targeting the angiotensin II type I receptor (AT1R) in microglia can combat cognitive impairment caused by chronic cerebral hypoperfusion (CCH). Blocking AT1R reduces neuroinflammation and improves brain function in vascular dementia models.

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.

Keywords:
AT1Rcandesartanchronic cerebral hypoperfusioncognitive impairmentinflammatory responses

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