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This project did not receive any specific public nor private funding. It has been possible only thanks to the goodwill and the collaborative effort of the researchers and institutions signing this paper. RG acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. RG is principal investigator from grant PGC2018-094017-B-I00 from AEI/FEDER, EU. AG is principal investigator of Instituto de Salud Carlos III (ISCIII) of Spain grants PI18/01557 and P21/00915 co-financed by the FEDER funds from European Union. JV is principal investigator of ISCIII grants PI18/01556 and PI21/00914 co-financed by FEDER funds from European Union, and Junta Andalucia grant US-1262734 co-financed by Programa OperativoFEDER 2014-2020. JJT is principal investigator of PID2019-103921 GB-I00 from the Spanish Ministerio de Ciencia e Innovacion. JLR is principal investigator of UMA20-FEDERJA-133 from the program FEDER Andalucia 2014-2020, EU. JLR also acknowledges the Centro de Supercomputacion y Bioinformatica (Picasso-server) for computing support. I. de Rojas is supported by national grant from the Instituto de Salud Carlos III FI20/00215. CM-C was supported by FPU fellowship from the Spanish Ministry of Science, Innovation, and Universities. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria "La Caixa", Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R+ D+ I Plan and funded by ISCIII (Instituto de Salud Carlos III) Subdirecci ' on General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-"Una manera de hacer Europa").

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An insertion within SIRPβ1 shows a dual effect over Alzheimer's disease cognitive decline altering the microglial response

Publicado en:JOURNAL OF ALZHEIMERS DISEASE. 98 (2): 601-618 - 2024-01-01 98(2), DOI: 10.3233/JAD-231150

Autores: García-Alberca, J.M.; …; Bullido, M.J.; …; The GERALD consortium

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Resumen

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRP beta 1, a surface receptor that triggers amyloid-beta(A beta) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRP beta 1 expression and howit 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. SIRP beta 1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRP beta 1 protein isoform landscape compromising its ability to bind oligomeric A beta and its affinity for TYROBP. SIRP beta 1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/A beta 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 SIRP beta 1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRP beta 1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to A beta. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRP beta 1 structural variant might be considered as a potential modulator of this causative pathway.

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