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.

It is well established that embryonic mouse retinal neurogenesis requiresNotch and Wnt signaling are also required for the development of vertebrate neural retina.This structure develops from a neuroepithelium composed of multipotent progenitors, which undergo a series of competence states to give rise to six neuronal and one glial cell types 2 . As progenitor cells produce the various cell types, Notch through lateral inhibition, maintains neighboring cells in a multipotent, proliferative state, ensuring that sufficient numbers of progenitors are retained for consecutive waves of neurogenesis. Thus, downregulation of Notch is a prerequisite for retinal neuronal differentiation 2 .Wnt/βcatenin signaling has also been implicated in the proliferation of vertebrate retinal precursors. However, in the mouse embryonic neural retina this function is limited to progenitor cells located in the periphery 3, 4 . In contrast, Wnt/βcatenin signaling is not active in the central retina and cell proliferation and differentiation proceed normally in mice with conditional deletion of βcatenin in the neural retina, although retinal lamination is altered 5 .Similarly, retinal specific inactivation of Fzd5, a non-canonical Wnt receptor mostly impacts on retinal vasculature formation but has no effect on neurogenesis 6 By analyzing the functional consequences of Sfrp1 and Sfrp2 compound inactivation during mouse retinal neurogenesis, we demonstrate here a novel and Wnt-independent role of Sfrps in the regulation of Notch signaling. We explain this finding by demonstrating that Sfrps can bind and downregulate the activity of ADAM10, a metalloprotease with multiple substrates including Notch, N-cadherin and APP. 4 RESULTS Sfrp1 and Sfrp2 are essential for proper eye developmentSfrp1 and Sfrp2 are expressed during murine eye development with a complementary pattern that includes all eye structures 7 . Sfrp1 transcripts are localized to the optic cup periphery and the retina pigmented epithelium from E10.5, while Sfrp2 is predominant in the neural retina (Fig. S1). Despite restricted mRNA expression, Sfrp proteins efficiently diffuse in the extracellular space 17 and Sfrp1 was immunodetected, albeit at low levels, also in the neural retina (Fig. S1), supporting the proposed Sfrp functional redundancy 9, 11, 12 .Accordingly, the eye of Sfrp1 and Sfrp2 single null embryos appeared histologically normal.In contrast at E16.5, the latest viable stage, the eyes of Sfrp1 -/-;Sfrp2 -/-compound mutants (n=20) were smaller than those of control littermates (n=30) with morphological visible alterations, including dorsal peripheral defects, reduction of the lens size, abnormal cornea and eye lid formation, increased thickness of the neural retina and abnormal vitreal accumulation of mesenchyme-derived angioblasts that normally form the hyaloid artery, the major vascular structure of the embryonic eye (Fig. S2). Inactivation of Sfrp1/2 alters retinal neurogenesisMultipotent progenitors in the neural retina generates neuronal and one glial cells wi...