SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Impaired neuronal and synaptic function are hallmarks of early Alzheimer's disease (AD), preceding other neuropathological traits and cognitive decline. We previously showed that SFRP1, a glial-derived protein elevated in AD brains from preclinical stages, contributes to disease progression, im...

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Detalles Bibliográficos
Autores: Pereyra, Guadalupe, Mateo, María Inés, Miaja, Pablo, Martin-Bermejo, María Jesús, Martinez-Baños, Marcos, Klaassen, Remco, Gruart, Agnès, Rueda-Carrasco, Javier, Fernández-Rodrigo, Alba, López-Merino, Esperanza, Esteve, Pilar, Esteban, José A., Smit, August B., Delgado-García, José M., Bovolenta, Paola
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::01377662e5737ca1d72b68a067ff0978
Acceso en línea:http://hdl.handle.net/10261/426275
Access Level:acceso abierto
Palabra clave:Alzheimer’s disease
astrocytes
dendritic spines
neurodegeneration
proteomics
structural synaptic molecules
synaptic plasticity
ADAM10
microglia
neurexin
Descripción
Sumario:Impaired neuronal and synaptic function are hallmarks of early Alzheimer's disease (AD), preceding other neuropathological traits and cognitive decline. We previously showed that SFRP1, a glial-derived protein elevated in AD brains from preclinical stages, contributes to disease progression, implicating glial factors in early pathogenesis. Here, we generate and analyze transgenic mice overexpressing astrocytic SFRP1. SFRP1 accumulation causes early dendritic and synaptic defects in adult mice, followed by impaired synaptic long-term potentiation and cognitive decline, evident only when the animals age, thereby mimicking AD's structural-functional temporal distinction. This phenotype correlates with proteomic changes, including increased structural synaptic proteins like neurexin, which localizes in close proximity with SFRP1 in cultured hippocampal neurons. We conclude that excessive SFRP1 hinders synaptic protein turnover, reducing synaptic plasticity—a mechanism that may underlie the synaptopathy observed in the brains of prodromal AD patients.

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