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

• Published in: Nature neuroscience Vol. 22; no. 8; pp. 1258 - 1268
• Main Authors: Esteve, Pilar, Rueda-Carrasco, Javier, Inés Mateo, María, Martin-Bermejo, María Jesús, Draffin, Jonathan, Pereyra, Guadalupe, Sandonís, África, Crespo, Inmaculada, Moreno, Inmaculada, Aso, Ester, Garcia-Esparcia, Paula, Gomez-Tortosa, Estrella, Rábano, Alberto, Fortea, Juan, Alcolea, Daniel, Lleo, Alberto, Heneka, Michael T., Valpuesta, José M., Esteban, José A., Ferrer, Isidro, Domínguez, Mercedes, Bovolenta, Paola
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2019; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/51; 13/95; 14/19; 14/28; 14/32; 14/34; 14/63; 38; 38/77; 45/29; 631/378/1689/364; 64/110; 64/60; 692/699/375/132/1283; 82/80; ADAM10 Protein - biosynthesis; ADAM10 Protein - genetics; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-protein; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases - biosynthesis; Amyloid Precursor Protein Secretases - genetics; Amyloidogenesis; Animal Genetics and Genomics; Animals; Antibodies; Antibodies, Blocking - therapeutic use; Axons; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain Chemistry - genetics; Causes of; Cerebrospinal fluid; Cognitive ability; Deactivation; Development and progression; Down-Regulation; Frizzled protein; Frizzled-related protein; Frizzled-related protein 1; Genetic aspects; Health aspects; Humans; Inactivation; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Long-Term Potentiation; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metalloproteinase; Mice; Mice, Transgenic; Neurites - pathology; Neurobiology; Neurosciences; Pathogenesis; Peptides; Plaque, Amyloid - drug therapy; Plaque, Amyloid - genetics; Plaque, Amyloid - pathology; Proteins; Secretase; Senile plaques; Therapeutic applications; Spain
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-019-0432-1

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. SFRP1, an ADAM10 inhibitor, is elevated in the brains of patients with Alzheimer’s disease (AD). Antibody-mediated neutralization of its activity stalls brain alterations and cognitive loss in AD-like mice, supporting SFRP1 as a potential target for disease therapy.