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

Abstract

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.

• Authors: Pilar Esteve, Javier Rueda-Carrasco, María Inés Mateo, María Jesús Martin-Bermejo, Jonathan Draffin, Guadalupe Pereyra, África Sandonís, Inmaculada Crespo, Inmaculada Moreno, Ester Aso, Paula Garcia-Esparcia, Estrella Gomez-Tortosa, Alberto Rábano, Juan Fortea, Daniel Alcolea, Alberto Lleo, Michael T Heneka, José M Valpuesta, José A Esteban, Isidro Ferrer, Mercedes Domínguez, Paola Bovolenta
• Journal: Nature neuroscience (Nat Neurosci) Vol. 22 Issue 8 Pg. 1258-1268 (08 2019) ISSN: 1546-1726 [Electronic] United States
• PMID: 31308530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• Antibodies, Blocking
• Intercellular Signaling Peptides and Proteins
• Membrane Proteins
• Sfrp1 protein, mouse
• Amyloid Precursor Protein Secretases
• ADAM10 Protein
• Adam10 protein, mouse

Topics

• ADAM10 Protein (biosynthesis, genetics)
• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid Precursor Protein Secretases (biosynthesis, genetics)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Antibodies, Blocking (therapeutic use)
• Brain Chemistry (genetics)
• Down-Regulation
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Long-Term Potentiation
• Membrane Proteins (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Mice
• Mice, Transgenic
• Neurites (pathology)
• Plaque, Amyloid (drug therapy, genetics, pathology)