Amyloid precursor protein is a subunit of microglial Hv1 channels.

Ruiming Zhao, Steve An Goldstein

Abstract readReview

In one paragraph

Review in Current opinion in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it

0cells of the map it votes in

0citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

2 authors.

Ruiming ZhaoDepartments of Pediatrics, Physiology & Biophysics, and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA. Electronic address: ruimiz3@uci.edu.

Steve An GoldsteinDepartments of Pediatrics, Physiology & Biophysics, and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA. Electronic address: sgoldst2@uci.edu.

Funding

hHv1 channels in neutrophils and the innate immune inflammatory responseR01HL159711 · NHLBI · UNIVERSITY OF CALIFORNIA-IRVINE · PI GOLDSTEIN, STEVE A N, ZHAO, RUIMING · 2022 to 2025

$2.4M

Identification of botanical hHv1 channel blockers as analgesics for neuropathic painR33AT012544 · NCCIH · UNIVERSITY OF CALIFORNIA-IRVINE · PI GOLDSTEIN, STEVE A N, WU, LONG-JUN · 2024 to 2025

$873k

Identification of botanical hHv1 channel blockers as analgesics for neuropathic painR61AT012544 · NCCIH · UNIVERSITY OF CALIFORNIA-IRVINE · PI GOLDSTEIN, STEVE A N, ZHAO, RUIMING · 2023 to 2023

$256k

NCCIH NIH HHS R33 AT012544NCCIH NIH HHS R61 AT012544NHLBI NIH HHS R01 HL159711

6 · The paper itself

Abstract

Voltage-gated proton channels (Hv1) are key regulators of microglial activation, coupling proton extrusion to reactive oxygen species production, cellular pH homeostasis, and pro-inflammatory signaling. Dysregulated Hv1 activity exacerbates neuroinflammation and contributes to a range of central nervous system pathologies. Our recent work shows that proton channels in microglia are formed by the co-assembly of Hv1 pore-forming subunits and amyloid precursor protein (APP). APP, and its C99 transmembrane fragment, assemble with Hv1 to enhance channel activity, altering gating kinetics, modifying pharmacological properties, and amplifying inflammatory mediator release from microglia. Importantly, Alzheimer's disease-associated APP mutations further potentiate Hv1 activity, providing a mechanistic link between genetic risk factors and microglial dysfunction, offering APP-Hv1 as a new therapeutic target for neuroinflammatory disease. This review summarizes current views of microglial Hv1 function and highlights that Hv1, long thought to operate as homodimers despite exhibiting varied attributes in native cells, exhibits functional diversity through accessory subunit incorporation.

Indexed as

Amyloid beta-Protein PrecursorIon ChannelsMicrogliaAlzheimer DiseaseAnimalsHumansMutationProtein SubunitsAmyloid beta-Protein PrecursorHVCN1 protein, humanIon ChannelsProtein Subunits

Identifiers

PMID41780099

DOI10.1016/j.coi.2026.102751

PMCPMC13274435

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.