Mechanobiological Specialization of Choroid Plexus Macrophages Defined by Titin Expression

Summary Functioning both as the site of cerebrospinal fluid production and as an interface between the peripheral circulation and the central nervous system, the choroid plexus (ChP) modulates the gating of immune cells and signals from the periphery as they pass from the blood into cerebrospinal fluid. We generated a single-nucleus and spatial transcriptomic atlas of the adult human ChP, in donors with and without Alzheimer’s disease (AD), revealing transcriptionally and spatially distinct macrophage states. We identified a previously unrecognized population of titin-expressing (TTN + ) tissue-resident macrophages characterized by coordinated activation of cytoskeletal remodeling, phagocytosis, autophagy, and inflammatory programs. Isoform-specific qPCR, protein immunofluorescence, and single-molecule FISH validated TTN expression in situ. In AD, TTN + macrophages expand and undergo broad transcriptional rewiring, including activation of MEF2-linked mechanotransduction pathways, elevated senescence signatures, and a loss of ligand–receptor connectivity with epithelial, endothelial, and stromal partners. Collectively, our findings define a mechanosensitive macrophage program at the blood–CSF interface and uncover a TTN-associated shift in macrophage function and microenvironment integration in AD.