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

Abstract

The deposition of aggregated Aβ peptides-derived from the pro-amyloidogenic processing of the Amyloid Precursor Protein (APP)-into characteristic amyloid plaques (APs) is distinctive to Alzheimer's disease (AD). Alternative APP processing via the metalloprotease ADAM10 prevents Aβ formation. We tested whether down-regulation of ADAM10 activity by its secreted endogenous inhibitor SFRP1 is a common trait of sporadic AD. We demonstrate that SFRP1 is significantly increased in the brain and cerebrospinal fluid of AD patients, accumulates in APs and binds to Aβ, hindering Aβ 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 favours non-amyloidogenic APP processing. Decreased Sfrp1 function lowers AP accumulation, improves AD-related histopathological traits and prevents LTP loss and cognitive deficits. Our study unveils SFRP1 as a crucial player in AD pathogenesis and a promising AD therapeutic target. donating a breeding pair of APP;PS1 mice and with J. Avila, C. Dotti, ML Toribio, S. Knafo and E. Palomer (CBMSO) for their advices during the course of this study. We also acknowledge the generosity of M.L de Ceballos, Instituto Cajal-CSIC, and M. Llorens, CBMSO, for sharing some tissue samples and C. Bovolenta (MolMed) for advice on lentiviral production. We thank O. Lancho and ML. Toribio for the Sfrp1 lentiviral construct and M. Guerra of the CBMSO EM facilities for help with TEM. We wish to thank C. Dotti, J. Garcia de Yébenes, S.R. de Cordoba (CIB-CSIC), C. Bovolenta and M. Nieto (CNB, CSIC) for critical reading the manuscript.

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

“…Besides highlighting a specific role of Sfrp1 in the adult retina, our study provides an additional physiological example in which Sfrp1 likely acts as an endogenous inhibitor of ADAM10, a conclusion that matches our previous findings (12,13,21,23). In homeostatic conditions, Sfrp1 expression is barely detectable in the cortex of young and healthy individuals but it expression increases with aging (70) and is upregulated in individual affected by Alzheimer's disease (13). In this condition, activated glial cells (particularly astrocytes) produce SFRP1 leading to increased levels of toxic products of amyloid precursor protein processing (13) and further sustaining chronic inflammation (15).…”

“…Instead, our data best explain the Sfrp1 -/retinal phenotype according to the following model ( Fig. 8), based on Sfrp1-mediated inhibition of the metalloprotease ADAM10 (12,13). Sfrp1, produced by photoreceptors and possibly Müller glial cells, downregulates ADAM10 activity at the OLM, thereby maintaining the required tight adhesion between the end-feet of Müller cells and the IS of the photoreceptors.…”

“…We thus reasoned that the retinal phenotype of the adult Sfrp1 -/mice could be mechanistically linked to poor Müller/photoreceptor cell adhesion, which, in turn, would be responsible of photoreceptor alterations. This mechanism is based on the notion that SFRP1 acts as a negative modulator of ADAM10 (12,13,21,23), which proteolytically removes the ectodomains (ectodomain shedding) of a large number membrane proteins (51), including cell adhesion molecules such as Cadherins and proto-Cadherins (52-54), thereby controlling cell-cell interactions (51,54).…”

“…In this context, we have recently shown that elevated levels of Secreted Frizzled-Related Protein (SFRP) 1-a secreted protein with the dual function of modulating Wnt signalling (11) and regulating the enzymatic activity of the α-sheddase ADAM10 (12)contributes to the pathogenesis of Alzheimer's Disease (13). Consistent with the notion that ADAM10 cleaves a large number of substrates -including the amyloid precursor protein (APP) and proteins involved in the activation of microglial cells and in synaptic plasticity (14)-, high levels of SFRP1 prevent ADAM10-mediated non-amyloidogenic processing of APP (13) and favour neuroinflammation (15). Sfrp1 and its homologues Sfrp2 and Sfrp5 have been implicated in different aspects of eye and retinal development (16)(17)(18)(19)(20)(21)(22).…”

“…Sfrp1 and its homologues Sfrp2 and Sfrp5 have been implicated in different aspects of eye and retinal development (16)(17)(18)(19)(20)(21)(22). Furthermore, and in contrast to what observed in the adult mammalian brain, in which expression is minimal in homeostatic conditions (13,23), SFRP1 and SFRP5 have been found expressed in the adult retina, mostly localized to the photoreceptor layer (24). SFRPs genes are an unlikely primary cause of RP in humans (25); however, their expression is notably increased and ectopically distributed in the retinas of individuals affected by RP (24,26).…”