An intragenic duplication withinSIRPβ1shows a dual effect over Alzheimer’s disease cognitive decline altering the microglial response
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 ,   The GERALD consortium, 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: November 2022

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 theSIRPβ1duplication 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 theSIRPβ1duplication allele correlates with higherTREM2expression 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.