Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer's disease pathogenesis
Por:
Esteve, P, Rueda-Carrasco, J, Mateo, MI, Martin-Bermejo, MJ, Draffin, J, Pereyra, G, Sandonis, A, Crespo, I, Moreno, I, Aso, E, Garcia-Esparcia, P, Gomez-Tortosa, E, Rabano, A, Fortea, J, Alcolea, D, Lleo, A, Heneka, MT, Valpuesta, JM, Esteban, JA, Ferrer, I, Dominguez, M, Bovolenta, P
Publicada:
1 ago 2019
Resumen:
The deposition of aggregated amyloid-beta 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-beta 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-beta, hindering amyloid-beta 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 alpha-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.
Filiaciones:
Esteve, P:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
CIBER Enfermedades Raras, Madrid, Spain
Rueda-Carrasco, J:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
CIBER Enfermedades Raras, Madrid, Spain
Mateo, MI:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
CIBER Enfermedades Raras, Madrid, Spain
Martin-Bermejo, MJ:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
CIBER Enfermedades Raras, Madrid, Spain
Draffin, J:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
Pereyra, G:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
CIBER Enfermedades Raras, Madrid, Spain
Sandonis, A:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
CIBER Enfermedades Raras, Madrid, Spain
Crespo, I:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
Moreno, I:
Inst Salud Carlos III, CNM, Unidad Inmunol Microbiana, Area Inmunol, Madrid, Spain
Aso, E:
Univ Barcelona, Hosp Univ Bellvitge, Bellvitge Biomed Res Inst, Neuropathol Inst, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Garcia-Esparcia, P:
Univ Barcelona, Hosp Univ Bellvitge, Bellvitge Biomed Res Inst, Neuropathol Inst, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Gomez-Tortosa, E:
Fdn Jimenez Diaz, Dept Neurol, Madrid, Spain
Rabano, A:
Alzheimer Ctr Reina Sofia Fdn, Fdn CIEN, Neuropathol Lab, Madrid, Spain
Fortea, J:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Dept Neurol, Barcelona, Spain
Alcolea, D:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Dept Neurol, Barcelona, Spain
Lleo, A:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Dept Neurol, Barcelona, Spain
Heneka, MT:
Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Esteban, JA:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
Univ Autonoma Madrid, CNB CSIC, Ctr Nacl Biotecnol, Madrid, Spain
Ferrer, I:
Univ Barcelona, Hosp Univ Bellvitge, Bellvitge Biomed Res Inst, Neuropathol Inst, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Dominguez, M:
Inst Salud Carlos III, CNM, Unidad Inmunol Microbiana, Area Inmunol, Madrid, Spain
Bovolenta, P:
Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain
CIBER Enfermedades Raras, Madrid, Spain
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