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oai:riuma.uma.es:10630/398952026-02-03T11:11:17Zcom_10630_2254col_10630_37953

Moreno-Madrid, Isabel Romero-Imbroda, Jesús Reyes-Bueno, José Antonio Arrabal-Gómez, José Carlos Díaz-Casares, Amelia Díaz-Sánchez, Estela Barbancho-Fernández, Miguel Ángel Fuxe, Kjell Borroto Escuela, Dasiel Óscar Serrano-Castro, Pedro Jesús Narváez-Peláez, Manuel 2025-09-15T08:42:32Z 2025-09-15T08:42:32Z 2025-07-02 Moreno-Madrid, I., Romero-Imbroda, J., Reyes-Bueno, J. A., Arrabal-Gómez, C., Díaz-Casares, A., Díaz-Sanchez, E., ... & Narváez, M. (2025). Peripheral expression of NPY1R-based heteroreceptor complexes reflects hippocampal neuroimmune status: Novel biomarkers for early Alzheimer’s disease detection. Biomedicine & Pharmacotherapy, 189, 118332 https://hdl.handle.net/10630/39895 10.1016/j.biopha.2025.118332 Alzheimer’s disease (AD) evolves from a prodromal phase with subtle neuroimmune disturbances to overt cognitive decline and hippocampal neurodegeneration. Detecting these early changes non-invasively remains a critical unmet need. Here we show that the abundance of neuropeptide-Y receptor-type-1 (NPY1R)–based heteroreceptor complexes(NPY1R–GALR2 and NPY1R–TrkB), quantified by proximity ligation assay (PLA), constitutes a peripheral read-out of hippocampal status across two complementary rat models. In an acute AccellsiRNA model that selectively knocked down NPY1R in the cerebroventricular space (8 days post-injection), both heterocomplexes were markedly reduced in the dentate gyrus and in circulating white-blood cells (WBCs), yet hippocampal neurogenesis (doublecortin⁺ cells) and object-in-place memory were still preserved, mimicking the pre-symptomatic/mild cognitive-impairment (MCI) stage of AD. Conversely, in a bilateral olfactory bulbectomy (OBX) model that reproduces chronic AD-like pathology (2 weeks post-surgery), the same heteroreceptor complexes were diminished centrally and peripherally, and this loss co-occurred with impaired object-in-place performance and a 25 % decrease in dentate gyrus neurogenesis. These findings demonstrate that peripheral NPY1R-based heteroreceptor levels mirror hippocampal neuroimmune alterations both before and after the emergence of cognitive and neurogenic deficits. A blood-based PLA assay targeting these complexes could therefore enable ultra-early AD screening, monitor disease progression, and guide the timely initiation of disease-modifying therapies. eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Alzheimer, Enfermedad de Neuropéptidos Marcadores bioquímicos Hipocampo (Cerebro) Neuroinmunología Peripheral expression of NPY1R-based heteroreceptor complexes reflects hippocampal neuroimmune status: Novel biomarkers for early Alzheimer’s disease detection. journal article