2025-10-23 カリフォルニア大学アーバイン校(UCI)
<関連情報>
- https://news.uci.edu/2025/10/23/uc-irvine-researchers-find-new-alzheimers-mechanism-linked-to-brain-inflammation/
- https://www.pnas.org/doi/10.1073/pnas.2509903122
アミロイド前駆体タンパク質とC99は、ヒトミクログリアHv1チャネルのサブユニットであり、電流と炎症性メディエーターの放出を促進する Amyloid precursor protein and C99 are subunits in human microglial Hv1 channels that enhance current and inflammatory mediator releas
Ruiming Zhao, Punyanuch Sophanpanichkul, Jean Paul Chadarevian, +5 , and Steve A. N. Goldstein
Proceedings of the National Academy of Sciences Published:October 23, 2025
DOI:https://doi.org/10.1073/pnas.2509903122
Significance
Microglial-mediated neuroinflammation is strongly implicated in the development and progression of Alzheimer’s disease (AD). Here we demonstrate that human induced pluripotent stem cell (iPSC)-microglia (iMG) employ voltage-gated proton channels (Hv1) to tightly regulate the production of proinflammatory mediators. Unexpectedly, AD-associated amyloid precursor protein (APP), assembles with Hv1 in iMG and promotes channel activity via its C99 transmembrane fragment. The inclusion of APP enhances Hv1 proton current, amplifying the release of inflammatory mediators, whereas knockdown of APP impairs microglial Hv1 function. Two AD-associated mutations in C99 also significantly increase channel activation beyond wild type C99 levels. Our findings demonstrate that native Hv1 channels deploy APP as an accessory subunit, providing insights into microglial function and highlighting a promising new therapeutic target.
Abstract
In Alzheimer’s disease (AD), hyperactivated microglia produce inflammatory mediators that contribute to neuroinflammation and neuronal damage. Amyloid precursor protein (APP), a transmembrane protein expressed in many cell types, including neurons and microglia, plays a critical role in AD pathogenesis via its secretase-mediated processing to release the C-terminal 99-residue transmembrane fragment (C99) that is further cleaved to yield amyloid-β peptides. Voltage-gated proton channels (Hv1) have been implicated in microglial activation and release of inflammatory mediators, but the potential role of these channels in human microglia and AD pathogenesis remains unclear. Here, we demonstrate that human induced pluripotent stem cell–derived microglia (iMG) express native Hv1 channels with biophysical and pharmacological attributes determined by their coassembly with APP and that APP knockdown decreases Hv1 currents, suppressing cytokine and reactive oxygen species release. In HEK293T cells, APP is shown to increase current by favoring channel opening at more negative membrane potentials. C99 is sufficient to assemble with Hv1 and alters channel function even more significantly than APP. Coimmunoprecipitation, total internal reflection fluorescence microscopy, and altered pharmacology further demonstrate that C99 forms stable complexes with Hv1 in the plasma membrane. In addition, we find that two early-onset AD mutations in APP (E682K and D694N) that reside within C99 significantly increase voltage-dependent channel activity beyond that induced by wild type C99, rationalizing their enhanced mediation of neuroinflammation.
