| Literature DB >> 31308530 |
Pilar Esteve1,2, Javier Rueda-Carrasco3,4, María Inés Mateo3,4, María Jesús Martin-Bermejo3,4, Jonathan Draffin3, Guadalupe Pereyra3,4, África Sandonís3,4, Inmaculada Crespo3, Inmaculada Moreno5, Ester Aso6,7, Paula Garcia-Esparcia6,7, Estrella Gomez-Tortosa8, Alberto Rábano9, Juan Fortea7,10, Daniel Alcolea7,10, Alberto Lleo7,10, Michael T Heneka11,12, José M Valpuesta13, José A Esteban3, Isidro Ferrer6,7, Mercedes Domínguez5, Paola Bovolenta14,15.
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.Entities:
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Year: 2019 PMID： 31308530 DOI： 10.1038/s41593-019-0432-1
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884