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Published on: July 29, 2022

ACE2 deficiency alters brain RAS signaling to induce pro-inflammatory microglial remodeling and Worsen Parkinson's

Tingting Liu1, Yuheng Ren2, Juntang Lin3

  • 1Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, China.

Neuroscience
|July 8, 2026
PubMed
Abstract

Insights

Parkinson's disease (PD) pathology is worsened by disrupted brain renin-angiotensin system (RAS) homeostasis, which drives pro-inflammatory microglial changes. This study uncovers new mechanisms and potential therapeutic targets for PD.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Parkinson's disease (PD) involves alpha-synuclein aggregation and dopaminergic neuron loss.
  • Microglia in the central nervous system (CNS) modulate inflammation in response to disease.
  • The cerebral renin-angiotensin system (RAS) influences PD, but its link to microglial inflammation is unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms connecting the brain's RAS to microglial inflammatory responses in Parkinson's disease.
  • To elucidate how ACE2 deficiency impacts RAS signaling and microglial activation in PD.

Main Methods:

  • Multi-omics analysis of public Parkinson's disease datasets.
  • In vitro studies using CRISPR-generated ACE2-knockout BV2 microglia.
  • In vivo experiments with MPTP-treated mice (wild-type and Ace2+/-).
  • Molecular techniques including western blot, immunohistochemistry, and immunofluorescence.

Main Results:

  • MPTP treatment induced pro-inflammatory microglial polarization.
  • ACE2 deletion disrupted cerebral RAS balance, increasing Ang II and AGTR1 levels.
  • Activated AGTR1 triggered multiple inflammatory signaling pathways (JAK1-STAT3-ERK, JNK-MAPK, PI3K-AKT-mTOR, Sirt1-FoxO1, TLR4-Myd88).
  • ACE2 deficiency exacerbated PD pathology via overactivated AGTR1 signaling, leading to increased neuronal injury markers.

Conclusions:

  • Disrupted brain RAS homeostasis promotes pro-inflammatory microglial remodeling, worsening PD neurodegeneration.
  • This research identifies novel pathogenic mechanisms in PD.
  • The study highlights potential therapeutic targets for Parkinson's disease treatment.
Keywords:
Angiotensin-converting enzyme 2ImmuneInflammationMicrogliaParkinson’s disease

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