Article
Author: Sánchez-Juan, Pascual ; Rodriguez-Rodriguez, Eloy ; García-Madrona, Sebastián ; Nieto, María Dolores ; González-Pérez, Antonio ; Alarcón-Martín, Emilio ; De la Guía, Paz ; Alegret, Montserrat ; Lage, Carmen ; López de la Rica, María ; del Ser, Teodoro ; Huerto Vilas, Raquel ; Roberto, Natalia ; Jiménez-Sánchez, Rocío ; Orellana, Adelina ; Hernández, Isabel ; Bernal Sánchez-Arjona, María ; Sanchez-Mejias, Elisabeth ; Sánchez-Fernández, Ana ; Sanabria, Ángela ; Gonzalez-Palma, Laura ; Torrecilla, Javier ; Fibla Palazon, Joan ; Garrido-Martín, Diego ; Piñol-Ripoll, Gerard ; Menéndez-González, Manuel ; Carracedo, Ángel ; Ruiz, Agustín ; Pineda, Juan A. ; Rueda, Lourdes ; Muñoz-Castro, Clara ; Macías, Juan ; Pérez-Cordón, Alba ; García-González, Pablo ; Calero, Miguel ; Espinosa, Ana ; Govantes, Fernando ; Rosende-Roca, Maitée ; García-Alberca, José María ; Martín Montes, Ángel ; Mendoza, Silvia ; Furniet, María del Carmen ; García-Peralta, María ; Vitorica, Javier ; Mejias-Ortega, Marina ; Urbano, Concepción ; Buiza-Rueda, Dolores ; Pino-Angeles, Almudena ; Peña, Isabel ; Laplana, Marina ; Moreno-Grau, Sonia ; Tena, Juan Jesus ; Martínez Rodríguez, Carmen ; Royo, Jose Luis ; Royo-Aguado, Jose Luis ; Quintela, Inés ; Cruz-Gamero, Jose Manuel ; Lopez, Aroa ; Carrillejo, Rosario ; Rosas Allende, Irene ; Navarro, Victoria ; de Rojas, Itziar ; Mancilla, Tomás ; Fernández-Fuertes, Marta ; Lopez-Gutierrez, Lidia ; Frank-García, Ana ; Marquié, Marta ; Tomas-Gallardo, Laura ; Gris, Esther ; Gutierrez, Antonia ; Diez-Fairen, Mónica ; Franco-Macías, Emilio ; Alvarez, Ignacio ; Tárraga, Lluís ; Medina, Miguel ; Gonzalez, Irene ; Rábano, Alberto ; Pastor, Ana Belén ; Álvarez, Victoria ; Corma-Gómez, Anaïs ; Pareja, Nuria ; Zafra, Carmen ; Mir, Pablo ; Boada, Mercè ; Polvillo, Rocio ; Pastor, Pau ; Ocejo, Olga ; Garcia-Ribas, Guillermo ; Ortega, Gemma ; Sotolongo-Grau, Oscar ; Valero, Sergi ; Montrreal, Laura ; Reyes-Engel, Armando ; Sáez, María Eugenia ; Arias Pastor, Alfonso ; Bullido, María José ; Real, Luis Miguel ; Guigo, Roderic ; Jimenez, Sebastian ; García-Casares, Natalia ; Luque, Macarena ; Ruiz, Maximiliano ; Bravo, Maria Jose
Background: Microglial dysfunction plays a causative role in Alzheimer’s disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.