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oai:riuma.uma.es:10630/371452026-02-03T11:21:44Zcom_10630_2254col_10630_37953
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Repositorio Institucional de la Universidad de Málaga author García-Alberca, JM author de Rojas, I author Sánchez-Mejías, Elisabeth author Garrido-Martín, D author Gonzalez-Palma, L author Jimenez, S author Pino-Angeles, A author Cruz-Gamero, JM author Mendoza, S author Alarcón-Martín, E author Muñoz-Castro, Clara author Real-Navarrete, Luis Miguel author Tena, Juan J. author Polvillo, R author Govantes, F author Lopez, A author Royo-Aguado, JL author Navarro, V author Gonzalez, I author Ruiz, M author Reyes-Engel, Armando author Gris, E author Bravo, MJ author Lopez-Gutierrez, L author Mejías-Ortega, Marina author De la Guía, María Paz author López de la Rica, M author Ocejo, Olga author Torrecilla, J author Zafra, C author Nieto, MD author Urbano, C author Jiménez-Sánchez, R author Pareja, N author Luque, M author García-Peralta, María author Carrillejo, Rosario author Furniet, MDC author Rueda, L author Sánchez-Fernández, A author Mancilla, T author Peña, I author García-Casares, N author Moreno-Grau, S author Hernández, I author Montrreal, L author Quintela, I author González-Pérez, A author Calero, M author Franco-Macías, Emilio author Macías, J author Menéndez-González, M author Frank-García, A author Huerto Vilas, R author Diez-Fairen, M author Lage, C author García-Madrona, S author García-González, P author Valero, S author Sotolongo-Grau, O author Pérez-Cordón, A author Rábano, A author Arias Pastor, A author Pastor, AB author Espinosa, A author Corma-Gómez, A author Martín Montes, A author Sanabria, A author Martínez Rodríguez, C author Buiza-Rueda, D author Rodriguez-Rodriguez, E author Ortega, G author Alvarez, I author Rosas Allende, I author Pineda, JA author Rosende-Roca, M author Bernal Sánchez-Arjona, M author Fernández-Fuertes, M author Alegret, M author Roberto, N author Del Ser, T author Garcia-Ribas, G author Sánchez-Juan, P author Pastor, P author Piñol-Ripoll, G author Bullido, MJ author Álvarez, V author Mir, P author Medina, M author Marquié, M author Sáez, ME author Carracedo, A author Laplana, M author Tomas-Gallardo, L author Orellana, A author Tárraga, LL author Boada, M author Fibla Palazon, J author Vitorica Ferrández, Javier author Ruiz, A author Guigo, R author Gutiérrez-Pérez, Antonia author Royo-Sánchez-Palencia, José Luis 2025-01-28T09:18:16Z 2025-01-28T09:18:16Z 2024 1. García-Alberca JM, de Rojas I, Sanchez-Mejias E, et al. An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer’s Disease Cognitive Decline Altering the Microglial Response. Journal of Alzheimer’s Disease. 2024;98(2):601-618. doi:10.3233/JAD-231150 https://hdl.handle.net/10630/37145 10.3233/JAD-231150 Microglia play an important role in the maintenance of brain homeostasis, and microglial dysfunction plays a causative role in Alzheimer disease pathogenesis. Here we focus on the signal regulatory protein SIRPβ1, a surface receptor expressed on the myeloid cells that triggers amyloid-β and cell debris phagocytosis via TYROBP. We found that a common intragenic duplication alters the SIRPβ1 protein isoform landscape affecting both extracellular and transmembrane domains, which compromise their ability to bind oligomeric Aβ and their affinity for TYROBP. Epidemiological studies show that patients with mild cognitive impairment that are homozygous for the SIRPβ1 duplication allele show an increased cerebrospinal fluid t-Tau/Aβ ratio (p-value=0.018) and a higher risk to develop AD (OR=1.678, p-value=0.018). Magnetic resonance imaging at diagnosis showed that AD patients with the duplication allele exhibited a worse initial response to the disease. At the moment of diagnosis all patients showed equivalent Mini-Mental State Examination scores. However AD patients with the duplication allele had less hippocampal degeneration (Beta= -0.62, p-value < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline after correcting by baseline (p-value = 0.013). Transcriptional analysis of the patients’ hippocampus also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Given the recent pharmacological approaches focused on the TREM2-TYROBP axis, we consider that the presence of this structural variant might be considered as a potential modulator of this causative pathway. eng Attribution-NonCommercial-NoDerivatives 4.0 Internacional Alzheimer, Enfermedad de Microglia - Investigación An intragenic duplication within SIRPβ1 shows a dual effect over Alzheimer’s disease cognitive decline altering the microglial response. journal article 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 URL https://riuma.uma.es/bitstreams/e5d05cf1-c46e-4b25-b35e-65438de070f8/download File MD5 bf20578d0c461222b714993195556f4f 1754700 application/pdf 2022.11.19.22282342.full.pdf