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

被引：56

作者：

Esteve, Pilar ^{[1
,2
]}

Rueda-Carrasco, Javier ^{[1
,2
]}

Ines Mateo, Maria ^{[1
,2
]}

Jesus Martin-Bermejo, Maria ^{[1
,2
]}

Draffin, Jonathan ^{[1
]}

Pereyra, Guadalupe ^{[1
,2
]}

Sandonis, Africa ^{[1
,2
]}

Crespo, Inmaculada ^{[1
]}

Moreno, Inmaculada ^{[3
]}

Aso, Ester ^{[4
,5
]}

Garcia-Esparcia, Paula ^{[4
,5
]}

Gomez-Tortosa, Estrella ^{[6
]}

Rabano, Alberto ^{[7
]}

Fortea, Juan ^{[8
]}

Alcolea, Daniel ^{[5
,8
]}

Lleo, Alberto ^{[5
,8
]}

Heneka, Michael T. ^{[9
,10
]}

Valpuesta, Jose M. ^{[11
]}

Esteban, Jose A. ^{[1
,11
]}

Ferrer, Isidro ^{[4
,5
]}

Dominguez, Mercedes ^{[3
]}

Bovolenta, Paola ^{[1
,2
]}

机构：

[1] Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain

[2] CIBER Enfermedades Raras, Madrid, Spain

[3] Inst Salud Carlos III, CNM, Unidad Inmunol Microbiana, Area Inmunol, Madrid, Spain

[4] Univ Barcelona, Hosp Univ Bellvitge, Bellvitge Biomed Res Inst, Neuropathol Inst, Barcelona, Spain

[5] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain

[6] Fdn Jimenez Diaz, Dept Neurol, Madrid, Spain

[7] Alzheimer Ctr Reina Sofia Fdn, Fdn CIEN, Neuropathol Lab, Madrid, Spain

[8] Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Dept Neurol, Barcelona, Spain

[9] Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany

[10] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany

[11] Univ Autonoma Madrid, CNB CSIC, Ctr Nacl Biotecnol, Madrid, Spain

来源：

NATURE NEUROSCIENCE | 2019年 / 22卷 / 08期

关键词：

AMYLOID PRECURSOR PROTEIN; ALPHA-SECRETASE; CEREBROSPINAL-FLUID; ADAM10; OLIGOMERS; MODEL; IMMUNOTHERAPIES; ACCUMULATION; EXPRESSION; PLASTICITY;

D O I：

10.1038/s41593-019-0432-1

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1258 / +

页数：14

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