| First Author | Esteve P | Year | 2019 |
| Journal | Nat Neurosci | Volume | 22 |
| Issue | 8 | Pages | 1258-1268 |
| PubMed ID | 31308530 | Mgi Jnum | J:281638 |
| Mgi Id | MGI:6378389 | Doi | 10.1038/s41593-019-0432-1 |
| Citation | Esteve P, et al. (2019) Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer's disease pathogenesis. Nat Neurosci 22(8):1258-1268 |
| abstractText | 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. |
