Portal de Periódicos da CAPES

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

2024; IOS Press; Volume: 98; Issue: 2 Linguagem: Inglês

10.3233/jad-231150

1875-8908

José María García‐Alberca, Itziar de Rojas, Elisabeth Sánchez‐Mejías, Diego Garrido-Martín, Laura Gonzalez-Palma, Sebastián Jiménez, Almudena Pino‐Ángeles, J. M. Cruz-Gamero, Silvia Mendoza, Emilio Alarcón‐Martín, Clara Muñoz‐Castro, Luís Miguel Real, Juan J. Tena, Rocío Polvillo, Fernando Govantes, Aroa Lopez, Jose Luis Royo-Aguado, Victoria Navarro, Irene González, Maximiliano Ruiz, Armando Reyes‐Engel, Esther Gris, María José Bravo, Lidia Lopez-Gutierrez, Marina Mejias‐Ortega, Paz de la Guía, María López de la Rica, Olga Ocejo, Javier Torrecilla, Carmen Zafra, María Dolores Nieto, Concepción Urbano, Rocío Jiménez-Sánchez, Nuria Pareja, Macarena Luque, María García-Peralta, Rosario Carrillejo, María del Carmen Furniet, Lourdes Rueda, Ana Sánchez-Fernández, Tomás Mancilla, Isabel Peña, Natalia García‐Casares, Sonia Moreno‐Grau, Isabel Hernández, Laura Montrreal, Inés Quintela, Antonio González‐Pérez, Miguel Calero, Emilio Franco‐Macías, Juan Macı́as, Manuel Menéndez‐González, Ana Frank, Raquel Huerto Vilas, Mónica Díez-Fairén, Carmen Lage, Sebastián García‐Madrona, Pablo García‐González, Sergi Valero, Óscar Sotolongo‐Grau, Alba Pérez‐Cordón, Alberto Rábano, Alfonso Arias Pastor, Ana Belén Pastor, Ana Espinosa, Anaïs Corma‐Gómez, Ángel Martín Montes, Ángela Sanabria, Carmen Martínez Rodríguez, Dolores Buiza‐Rueda, Eloy Rodríguez‐Rodríguez, Gemma Ortega, Ignacio Álvarez, Irene Rosas Allende, Juan A. Pineda, Maitée Rosende‐Roca, María Bernal Sánchez-Arjona, Marta Fernández‐Fuertes, Montserrat Alegret, Natalia Roberto, Teodoro del Ser, Guillermo García‐Ribas, Pascual Sánchez‐Juan, Pau Pástor, Gerard Piñol‐Ripoll, María José Bullido, Victoria Álvarez, Pablo Mir, Miguel Medina, Marta Marquié, María Eugenia Sáez, Ángel Carracedo, Marina Laplana, Laura Tomás‐Gallardo, Adelina Orellana, Lluís Tárraga, Merçé Boada, Joan Fibla i Palazón, Javier Vitórica, Agustı́n Ruiz, Roderic Guigó, Antonia Gutiérrez, José Luís Royo,

Inflammation biomarkers and pathways

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.