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

José María García-Alberca, Itziar De Rojas, Elisabeth Sanchez-Mejias, Diego Garrido-Martín, Laura Gonzalez-Palma, Sebastian Jimenez, Almudena Pino-Angeles, Jose Manuel Cruz-Gamero, Silvia Mendoza, Emilio Alarcón-Martín, Clara Muñoz-Castro, Luis Miguel Real, Juan Jesus Tena, Rocio Polvillo, Fernando Govantes, Aroa Lopez, Jose Luis Royo-Aguado, Victoria Navarro, Irene Gonzalez, Maximiliano RuizArmando Reyes-Engel, Esther Gris, Maria Jose 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 MacÍas, Manuel Menéndez-González, Ana Frank-García, Raquel Huerto Vilas, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Sergi Valero, Oscar 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 Rodriguez-Rodriguez, Gemma Ortega, Ignacio Alvarez, Irene Rosas Allende, Juan A. Pineda, Maitée Rosende-Roca, María Bernal Sánchez-Arjona, Marta Fernández-Fuertes, Montserrat Alegret, Natalia Roberto, Teodoro Del Ser, Guillermo Garcia-Ribas, Pascual Sánchez-Juan, Pau Pastor, Gerard Piñol-Ripoll, María José Bullido, Victoria Álvarez, Pablo Mir, Miguel Medina, Marta Marquié, María Eugenia Sáez, Ángel Carracedo, Marina Laplana, Laura Tomas-Gallardo, Adelina Orellana, Lluís Tárraga, Mercè Boada, Joan Fibla Palazon, Javier Vitorica, Agustín Ruiz, Roderic Guigo, Antonia Gutierrez, Jose Luis Royo, Steve Estus

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)601-618
Number of pages18
JournalJournal of Alzheimer's Disease
Volume98
Issue number2
DOIs
StatePublished - Mar 19 2024

Bibliographical note

Publisher Copyright:
© 2024-IOS Press. All rights reserved.

Keywords

  • Alzheimer's disease
  • DAP12
  • SIRPβ1
  • TREM2
  • TYROBP
  • copy-number variant
  • microglia

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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