| Title: |
An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response. |
| Authors: |
García-Alberca, Jose 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 Aguilar, 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; Moreno-Grau, Sonia; García-Casares, Natalia; 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 Lafaja, Marina; Tomas-Gallardo, Laura; Orellana, Adelina; Tárraga, Lluís; Boada, Mercè; Fibla Palazón, Joan; Vitorica, Javier; Ruiz, Agustín; Guigo, Roderic; Gutierrez, Antonia; Royo Sánchez-Palencia, José Luis |
| Contributors: |
GERALD consortium |
| Publisher Information: |
IOS Press |
| Publication Year: |
2024 |
| Collection: |
Universitat de Lleida: Repositori Obert UdL |
| Subject Terms: |
Alzheimer’s disease; Copy-number variant; DAP12; Microglia; SIRPβ1; TREM2; TYROBP |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Versió postprint del document publicat a: https://doi.org/10.3233/JAD-231150; Journal of Alzheimer's Disease, 2024, vol. 98, núm. 2, p. 601-618; https://hdl.handle.net/10459.1/465873 |
| DOI: |
10.3233/JAD-231150 |
| Availability: |
https://hdl.handle.net/10459.1/465873; https://doi.org/10.3233/JAD-231150 |
| Rights: |
(c) Authors, 2024 ; info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.C9731487 |
| Database: |
BASE |