An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer’s Disease Cognitive Decline Altering the Microglial Response

• Published in: Journal of Alzheimer's disease 2024-01, Vol.98 (2), p.601-618
• Main Authors: García-Alberca, José María, de Rojas, Itziar, Sanchez-Mejias, Elisabeth, Garrido-Martín, Diego, Gonzalez-Palma, Laura, Jimenez, Sebastian, Pino-Angeles, Almudena, Cruz-Gamero, Jose Manuel, Mendoza, Silvia, Alarcón-Martín, Emilio, Muñoz-Castro, Clara, Real, Luis Miguel, Tena, Juan Jesus, Polvillo, Rocio, Govantes, Fernando, Lopez, Aroa, Royo-Aguado, Jose Luis, Navarro, Victoria, Gonzalez, Irene, Ruiz, Maximiliano, Reyes-Engel, Armando, Gris, Esther, Bravo, Maria Jose, Lopez-Gutierrez, Lidia, Mejias-Ortega, Marina, De la Guía, Paz, López de la Rica, María, Ocejo, Olga, Zafra, Carmen, Nieto, María Dolores, Urbano, Concepción, Jiménez-Sánchez, Rocío, Pareja, Nuria, Luque, Macarena, García-Peralta, María, Carrillejo, Rosario, Furniet, María del Carmen, Rueda, Lourdes, Sánchez-Fernández, Ana, Mancilla, Tomás, Peña, Isabel, García-Casares, Natalia, Moreno-Grau, Sonia, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, González-Pérez, Antonio, Calero, Miguel, Franco-Macías, Emilio, Macías, Juan, Frank-García, Ana, Huerto Vilas, Raquel, Diez-Fairen, Mónica, Lage, Carmen, García-Madrona, Sebastián, García-González, Pablo, Valero, Sergi, Sotolongo-Grau, Oscar, Pérez-Cordón, Alba, Rábano, Alberto, Arias Pastor, Alfonso, Pastor, Ana Belén, Espinosa, Ana, Corma-Gómez, Anaïs, Martín Montes, Ángel, Sanabria, Ángela, Martínez Rodríguez, Carmen, Buiza-Rueda, Dolores, Rodriguez-Rodriguez, Eloy, Ortega, Gemma, Alvarez, Ignacio, Pineda, Juan A., Rosende-Roca, Maitée, Bernal Sánchez-Arjona, María, Fernández-Fuertes, Marta, Alegret, Montserrat, Roberto, Natalia, del Ser, Teodoro, Garcia-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Piñol-Ripoll, Gerard, Bullido, María José, Álvarez, Victoria, Mir, Pablo, Medina, Miguel, Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Laplana, Marina, Tomas-Gallardo, Laura, Orellana, Adelina, Tárraga, Lluís, Boada, Mercè, Fibla Palazon, Joan, Vitorica, Javier, Ruiz, Agustín, Guigo, Roderic, Gutierrez, Antonia, Royo, Jose Luis
• Format: Article
• Language: English
• Subjects: Alleles; Alzheimer's disease; Cerebrospinal fluid; Cognitive ability; Degeneration; Dementia disorders; Hippocampus; Impact analysis; Insertion; Longitudinal studies; Neurodegenerative diseases; Pathogenesis; Phagocytosis; Substantia alba; Tau protein; β-Amyloid
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-231150

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