[en] 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.
Disciplines :
Neurology
Author, co-author :
Esteve, Pilar ; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain. pesteve@cbm.csic.es ; CIBER de Enfermedades Raras, Madrid, Spain. pesteve@cbm.csic.es
Rueda-Carrasco, Javier ; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain ; CIBER de Enfermedades Raras, Madrid, Spain
Inés Mateo, María; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain ; CIBER de Enfermedades Raras, Madrid, Spain
Martin-Bermejo, María Jesús; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain ; CIBER de Enfermedades Raras, Madrid, Spain
Draffin, Jonathan; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain
Pereyra, Guadalupe; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain ; CIBER de Enfermedades Raras, Madrid, Spain
Sandonís, África; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain ; CIBER de Enfermedades Raras, Madrid, Spain
Crespo, Inmaculada; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain
Moreno, Inmaculada; Unidad de Inmunología Microbiana, Área de Inmunología, CNM, Instituto de Salud Carlos III, Madrid, Spain
Aso, Ester; Neuropathology Institute, Bellvitge Biomedical Research Institute, Hospital Universitari de Bellvitge, Universitat de Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Garcia-Esparcia, Paula; Neuropathology Institute, Bellvitge Biomedical Research Institute, Hospital Universitari de Bellvitge, Universitat de Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Gomez-Tortosa, Estrella; Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain
Fortea, Juan; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain ; Department of Neurology, Institut Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, Barcelona, Spain
Alcolea, Daniel; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain ; Department of Neurology, Institut Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, Barcelona, Spain
Lleo, Alberto ; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain ; Department of Neurology, Institut Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, Barcelona, Spain
HENEKA, Michael ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Valpuesta, José M ; Centro Nacional de Biotecnología, CNB-CSIC, Universidad Autónoma de Madrid, Madrid, Spain
Esteban, José A ; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain
Ferrer, Isidro; Neuropathology Institute, Bellvitge Biomedical Research Institute, Hospital Universitari de Bellvitge, Universitat de Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Domínguez, Mercedes; Unidad de Inmunología Microbiana, Área de Inmunología, CNM, Instituto de Salud Carlos III, Madrid, Spain
Bovolenta, Paola ; Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain. pbovolenta@cbm.csic.es ; CIBER de Enfermedades Raras, Madrid, Spain. pbovolenta@cbm.csic.es
We are in debt to I. Torres-Aleman, Instituto Cajal-CSIC, for donating a breeding pair of APP;PS1 mice and to J. Avila, C. Dotti, M.L. Toribio, S. Knafo and E. Palomer (CBMSO) for their advice during the course of this study. We also acknowledge the generosity of M.L. de Ceballos, Instituto Cajal-CSIC, and M. Llorens, CBMSO, for sharing some tissue samples and C. Bovolenta (MolMed) for advice on lentiviral production. We thank O. Lancho and M.L. Toribio for the Sfrp1 lentiviral construct and M. Guerra of the CBMSO EM facilities for help with TEM. We wish to thank C. Dotti, J. Garcia de Yébenes, S.R. de Cordoba (CIB-CSIC), C. Bovolenta and M. Nieto (CNB, CSIC) for critical reading the manuscript. This work was supported by grants from the Spanish MINECO (nos. BFU2013-43213-P and BFU2016-75412-R with FEDER support), the Fundación Tatiana Perez de Guzman el Bueno and CIBERER with grants to P.B. and P.E., and grant no. FIS PI11/3035 to A.L. J.R.C. (grant no. BES-2011-047189), M.I.M. (no. BES-2014-068797) and G.P. (no. BES-2017-080318) were supported by FPI fellowships from the MINECO. We also acknowledge a CBMSO Institutional grant from the Fundación Ramon Areces.
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