Amyloid precursor protein is a subunit of microglial Hv1 channels

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.