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Updated: Apr 23, 2026

Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease

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Gut microbial metabolite indole-3-acetic acid inhibits microglia-mediated synaptic loss in Alzheimer's disease by

Tao Ye1, Xinhuang Lv1, Qiyao Li1

  • 1Department of Neurology, the Second Affiliated Hospital of Wenzhou Medical University, 325027 Wenzhou, Zhejiang, China.

Brain, Behavior, and Immunity
|April 21, 2026
PubMed

Insights

Alzheimer's disease (AD) is linked to low indole-3-acetic acid (IAA) levels. Supplementing IAA and targeting C-C chemokine receptor 4 (CCR4) in microglia may offer new therapeutic strategies for AD.

Area of Science:

  • Neuroscience
  • Microbiology
  • Immunology

Background:

  • Gut microbial metabolites are implicated in Alzheimer's disease (AD) progression.
  • The precise mechanisms linking these metabolites to AD pathogenesis remain unclear.

Purpose of the Study:

  • To investigate the role of indole-3-acetic acid (IAA), a gut microbial metabolite, in AD.
  • To elucidate the molecular mechanisms by which IAA influences AD pathology, focusing on microglial function and synaptic integrity.

Main Methods:

  • Analysis of IAA levels in AD patients and correlation with cognitive impairment.
  • In vivo (mouse models) and in vitro (cell models) experiments using IAA supplementation.
  • RNA sequencing to identify key regulatory pathways and targets.
  • Investigating the interaction between C-C chemokine receptor 4 (CCR4), aryl hydrocarbon receptor (AHR), and microglial phagocytosis.

Main Results:

  • Decreased IAA levels were observed in AD patients and correlated with cognitive decline.
  • IAA supplementation ameliorated cognitive dysfunction, reduced synaptic damage, and suppressed microglial activation and synaptic phagocytosis in AD models.
  • RNA sequencing identified increased phagocytosis-associated pathways, with CCR4 identified as a key regulator.
  • IAA inhibited CCR4 expression, while CCR4 inhibition reduced microglia-mediated synaptic phagocytosis.
  • Aryl hydrocarbon receptor (AHR) was found to interact with microglial CCR4, potentially inhibiting its transcription.

Conclusions:

  • Gut microbial metabolite IAA plays a protective role in Alzheimer's disease by modulating microglial activity.
  • The mechanism involves IAA's interaction with AHR to down-regulate CCR4, thereby inhibiting microglia-mediated synaptic phagocytosis.
  • Targeting CCR4 in microglia presents a potential therapeutic strategy for mitigating synaptic loss and delaying Alzheimer's progression.
Keywords:
Alzheimer’sdiseaseArylhydrocarbonreceptorC-Cchemokinereceptor4Indole-3-aceticacidMicrogliaSynapticphagocytosis

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