Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis

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 form...

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Detalles Bibliográficos
Autores: Esteve, Pilar, Rueda-Carrasco, Javier, Mateo, María I., Martín-Bermejo, María Jesús, Draffin, Jonathan E., Pereyra, Guadalupe, Sandonís, África, Crespo, Inmaculada, Moreno, Inmaculada, Aso, Ester, García-Esparcia, Paula, Gómez-Tortosa, Estrella, Rábano, Alberto, Fortea, Juan, Alcolea, Daniel, Lleó, Alberto, Heneka, Michael T., Valpuesta, José M., Esteban, José A., Ferrer, Isidro, Domínguez, Mercedes, Bovolenta, Paola
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/193936
Acceso en línea:http://hdl.handle.net/10261/193936
Access Level:acceso abierto
Palabra clave:ddc:570
Descripción
Sumario: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.

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