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Updated: Mar 6, 2026

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
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Amyloid precursor protein is a subunit of microglial Hv1 channels

Ruiming Zhao1, Steve An Goldstein1

  • 1Departments of Pediatrics, Physiology & Biophysics, and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA.

Current Opinion in Immunology
|March 4, 2026
PubMed

Insights

Voltage-gated proton channels (Hv1) in microglia are regulated by amyloid precursor protein (APP). APP enhances Hv1 activity, linking Alzheimer's disease mutations to neuroinflammation and offering a new therapeutic target.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Immunology

Background:

  • Voltage-gated proton channels (Hv1) regulate microglial activation, impacting neuroinflammation and CNS pathologies.
  • Dysregulated Hv1 activity is implicated in various central nervous system disorders.

Purpose of the Study:

  • To investigate the role of amyloid precursor protein (APP) in modulating Hv1 channel function in microglia.
  • To explore the therapeutic potential of targeting the APP-Hv1 interaction in neuroinflammatory diseases.

Main Methods:

  • Co-assembly analysis of Hv1 and APP subunits.
  • Electrophysiological characterization of Hv1 channel activity.
  • Assessment of inflammatory mediator release from microglia.

Main Results:

  • APP and its C99 fragment co-assemble with Hv1, enhancing channel activity and altering gating kinetics.
  • APP-Hv1 interaction amplifies inflammatory mediator release from microglia.
  • Alzheimer's disease-associated APP mutations potentiate Hv1 activity, linking genetic risk to microglial dysfunction.

Conclusions:

  • The APP-Hv1 complex represents a novel mechanism regulating microglial function and neuroinflammation.
  • Targeting the APP-Hv1 interaction offers a promising therapeutic strategy for neuroinflammatory diseases, including Alzheimer's disease.

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