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.

Neuroinflammation is a common feature of many neurodegenerative diseases. It fosters a dysfunctional neuron-microglia-astrocyte crosstalk that, in turn, maintains microglial cells in a perniciously reactive state that often enhances neuronal damage. The molecular components that mediate this critical communication are not fully explored. Here, we show that secreted frizzled-related protein 1 (SFRP1), a multifunctional regulator of cell-to-cell communication, is part of the cellular crosstalk underlying neuroinflammation. In mouse models of acute and chronic neuroinflammation, SFRP1, largely astrocyte-derived, promotes and sustains microglial activation, and thus a chronic inflammatory state. SFRP1 promotes the upregulation of components of the hypoxia-induced factordependent inflammatory pathway and, to a lower extent, of those downstream of the nuclear factor-kappa B. We thus propose that SFRP1 acts as an astrocyte-to-microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation in several neurodegenerative diseases.