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Título: | Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis |
Autor: | Esteve, Pilar CSIC ORCID; Rueda-Carrasco, Javier; Mateo, María I.; Martín-Bermejo, María Jesús CSIC; Draffin, Jonathan E. CSIC ORCID; Pereyra, Guadalupe; Sandonís, África; Crespo, Inmaculada; Moreno, Inmaculada CSIC ORCID; Aso, Ester; García-Esparcia, Paula; Gómez-Tortosa, Estrella; Rábano, Alberto; Fortea, Juan; Alcolea, Daniel; Lleó, Alberto; Heneka, Michael T.; Valpuesta, José M. CSIC ORCID ; Esteban, José A. CSIC ORCID; Ferrer, Isidro; Domínguez, Mercedes; Bovolenta, Paola CSIC ORCID | Fecha de publicación: | ago-2019 | Citación: | Nature Neuroscience | Resumen: | The deposition of aggregated amyloid-β peptides derived from the pro-amyloidogenic processing of the amyloid precurson protein (APP) into characteristic amyloid plaques (APs) is distinctive to Alzheimer’s disease (AD). Alternative APP processing via the metalloprotease ADAM10 prevents amyloid-β formation. We tested whether downregulation of ADAM10 activity by its secreted endogenous inhibitor secreted-frizzled-related protein 1 (SFRP1) is a common trait of sporadic AD. We demonstrate that SFRP1 is significantly increased in the brain and cerebrospinal fluid of patients with AD, accumulates in APs and binds to amyloid-β, hindering amyloid-β protofibril formation. Sfrp1 overexpression in an AD-like mouse model anticipates the appearance of APs and dystrophic neurites, whereas its genetic inactivation or the infusion of α-SFRP1-neutralizing antibodies favors non-amyloidogenic APP processing. Decreased Sfrp1 function lowers AP accumulation, improves AD-related histopathological traits and prevents long-term potentiation loss and cognitive deficits. Our study unveils SFRP1 as a crucial player in AD pathogenesis and a promising AD therapeutic target. | Versión del editor: | 10.1038/s41593-019-0432-1 | URI: | http://hdl.handle.net/10261/193936 | ISSN: | 1097-6256 |
Aparece en las colecciones: | (CBM) Artículos (CNB) Artículos |
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BovolentaP_ElevatedLevelsofSecreted.pdf | Articulo principal | 1,73 MB | Adobe PDF | Visualizar/Abrir |
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