An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer’s Disease Cognitive Decline Altering the Microglial Response
Authors: García-Alberca José María ,   The GERALD consortium, 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 , Torrecilla Javier , 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 , Menéndez-González Manuel , 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 , Rosas Allende Irene , 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 
Published: February 2024

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.