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

Article type: Research Article

Authors: García-Alberca, José María^{a; 1; *} | de Rojas, Itziar^{b; c; 1} | Sanchez-Mejias, Elisabeth^{c; d; 1} | Garrido-Martín, Diego^{e; f} | Gonzalez-Palma, Laura^g | Jimenez, Sebastian^{c; h; i} | Pino-Angeles, Almudena^{j; k} | Cruz-Gamero, Jose Manuel^{g; l} | Mendoza, Silvia^a | Alarcón-Martín, Emilio^{b; c; g} | The GERALD consortium^m | Muñoz-Castro, Clara^{c; h; i} | Real, Luis Miguel^{g; n} | Tena, Juan Jesus^o | Polvillo, Rocio^o | Govantes, Fernando^o | Lopez, Aroa ^o | Royo-Aguado, Jose Luis^p | Navarro, Victoria^{c; h; i} | Gonzalez, Irene^g | Ruiz, Maximiliano^g | Reyes-Engel, Armando^g | Gris, Esther^a | Bravo, Maria Jose^g | Lopez-Gutierrez, Lidia^{g; q} | Mejias-Ortega, Marina^{c; d} | De la Guía, Paz^a | López de la Rica, María^a | Ocejo, Olga^r | Torrecilla, Javier^r | Zafra, Carmen^r | Nieto, María Dolores^s | Urbano, Concepción^s | Jiménez-Sánchez, Rocío^s | Pareja, Nuria^t | Luque, Macarena^u | García-Peralta, María^u | Carrillejo, Rosario^v | Furniet, María del Carmen^w | Rueda, Lourdes^w | Sánchez-Fernández, Ana^x | Mancilla, Tomás^x | Peña, Isabel^x | García-Casares, Natalia^y | Moreno-Grau, Sonia^{b; c} | Hernández, Isabel^{b; c} | Montrreal, Laura^b | Quintela, Inés^z | González-Pérez, Antonio^aa | Calero, Miguel^{c; bb; cc} | Franco-Macías, Emilio^dd | Macías, Juanⁿ | Menéndez-González, Manuel^{ee; ff; gg} | Frank-García, Ana^hh | Huerto Vilas, Raquel^{ii; jj} | Diez-Fairen, Mónica^{kk; ll} | Lage, Carmen^mm | García-Madrona, Sebastiánⁿⁿ | García-González, Pablo^{b; c} | Valero, Sergi^{b; c} | Sotolongo-Grau, Oscar^b | Pérez-Cordón, Alba^b | Rábano, Alberto^bb | Arias Pastor, Alfonso^{ii; jj} | Pastor, Ana Belén^bb | Espinosa, Ana^{b; c} | Corma-Gómez, Anaïsⁿ | Martín Montes, Ángel^{c; hh; oo} | Sanabria, Ángela^{b; c} | Martínez Rodríguez, Carmen^pp | Buiza-Rueda, Dolores^{c; qq} | Rodriguez-Rodriguez, Eloy^{c; rr} | Ortega, Gemma^{b; c} | Alvarez, Ignacio^kk | Rosas Allende, Irene^ss | Pineda, Juan A.ⁿ | Rosende-Roca, Maitée^{b; c} | Bernal Sánchez-Arjona, María^dd | Fernández-Fuertes, Martaⁿ | Alegret, Montserrat^{b; c} | Roberto, Natalia^b | del Ser, Teodoro^bb | Garcia-Ribas, Guillermoⁿⁿ | Sánchez-Juan, Pascual^bb | Pastor, Pau^kk | Piñol-Ripoll, Gerardⁱⁱ | Bullido, María José^{c; tt} | Álvarez, Victoria^ss | Mir, Pablo^{c; qq; uu} | Medina, Miguel^{c; bb} | Marquié, Marta^{b; c} | Sáez, María Eugenia^aa | Carracedo, Ángel^{z; vv} | Laplana, Marina^{jj; ww} | Tomas-Gallardo, Laura^xx | Orellana, Adelina^{b; c} | Tárraga, Lluís^{b; c} | Boada, Mercè^{b; c} | Fibla Palazon, Joan^{jj; ww} | Vitorica, Javier^{c; h; i} | Ruiz, Agustín^{b; c} | Guigo, Roderic^e | Gutierrez, Antonia^{c; d} | Royo, Jose Luis^{g; *}

Affiliations: [a] Alzheimer Research Center and Memory Clinic, Instituto Andaluz de Neurociencia (IANEC), Málaga, Spain | [b] Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain | [c] CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain | [d] Departamento Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Instituto de Investigacion Biomedica de Malaga-IBIMA, Universidad de Málaga, Málaga, Spain | [e] Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain | [f] Section of Statistics, Faculty of Biology, Universitat de Barcelona (UB), Barcelona, Spain | [g] Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain | [h] Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain | [i] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio CSIC, Universidad de Sevilla, Seville, Spain | [j] Unidad de Lípidos y Arteriosclerosis, Servicio de Medicina Interna, Hospital Universitario Reina Sofia, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain | [k] Centro de Investigación Biomédicaen Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain | [l] Institute of Psychiatry and Neuroscience of Paris, Université de Paris, INSERM U1266, Paris, France | [m] GERALD Consortium | [n] Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain | [o] Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide/Consejo Superior de Investigaciones Científicas/Junta de Andalucía, Sevilla, Spain | [p] Instituto SantÁngela, Sevilla, Spain | [q] Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience, Institute (UNI), Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium | [r] Centro Residencial Almudena, Malaga, Spain | [s] Hospital Hermanas Hospitalarias del Sagrado Corazón, Málaga, Spain | [t] Asociación de Familiares de Enfermos de Alzheimer de la Axarquía, Vélez-Málaga, Spain | [u] Centro Residencial Élite, Málaga, Spain | [v] Asociación Criptana de Enfermos de Alzheimer, Campo de Criptana, Spain | [w] Asociación de Familiares de Alzheimer de Archidona, Archidona, Spain | [x] Residencia DomusViFuentesol, Alhaurín de la Torre, Spain | [y] Departamento de Medicina, Facultad de Medicina, Universidad de Málaga, Málaga, Spain | [z] Fundación Pública Galega de Medicina Xenómica, Centro Nacional de Genotipado, IDIS, Santiago de Compostela, Spain | [aa] Centro Andaluz de Estudios Bioinformáticos (CAEBI), Sevilla, Spain | [bb] CIEN Foundation/Queen Sofia Foundation Alzheimer Center, Madrid, Spain | [cc] Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain | [dd] Unidad de Demencias, Servicio de Neurología y Neurofisiología, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain | [ee] Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain | [ff] Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain | [gg] Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain | [hh] Department of Neurology, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, IdiPAZ, La Paz University Hospital, Madrid, Spain | [ii] Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Lleida, Spain | [jj] Institut de Recerca Biomedica de Lleida (IRBLLeida), Lleida, Spain | [kk] Department of Neurology, Unit of Neurodegenerative Diseases, Hospital Universitari Germans Triasi Pujol and Germans Triasi Pujol Research Institute (IGTP) Badalona, Barcelona, Spain | [ll] Department of Neurology, Memory Disorders Unit, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain | [mm] Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain | [nn] Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain | [oo] Department of Neurology, La Paz University Hospital, Madrid, Spain | [pp] Hospital de Cabueñes, Gijón, Spain | [qq] Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain | [rr] Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain | [ss] Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain | [tt] Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain | [uu] Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain | [vv] Grupo de Medicina Xenómica CIBERER-CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain | [ww] Departament de Ciencies Mediques Basiques, Universitat de Lleida, Lleida, Spain | [xx] Proteomics and Biochemistry Unit, Andalusian Centre for Developmental Biology, CSIC-Pablo de Olavide University, Seville, Spain

Correspondence: [*] Correspondence to: Jose Luis Royo, Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología. Facultad de Medicina. Universidad de Málaga. Málaga, Spain. E-mail: jlroyo@uma.es and José María García-Alberca, Alzheimer Research Center and Memory Clinic. Instituto Andaluz de Neurociencia (IANEC), Málaga, Spain. E-mail: jmgalberca@ianec.com.

Note: [1] These authors contributed equally to this work.

Abstract: 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.

Keywords: Alzheimer’s disease, copy-number variant, DAP12, microglia, SIRPβ1, TREM2, TYROBP

DOI: 10.3233/JAD-231150

Journal: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 601-618, 2024