SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-04-22 Epub Date: 2025-04-07 DOI:10.1016/j.celrep.2025.115535

Guadalupe Pereyra, María Inés Mateo, Pablo Miaja, María Jesús Martin-Bermejo, Marcos Martinez-Baños, Remco Klaassen, Agnès Gruart, Javier Rueda-Carrasco, Alba Fernández-Rodrigo, Esperanza López-Merino, Pilar Esteve, José A Esteban, August B Smit, José M Delgado-García, Paola Bovolenta

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引用次数: 0

Abstract

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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SFRP1上调导致海马突触功能障碍和记忆障碍。

神经元和突触功能受损是早期阿尔茨海默病（AD）的特征，它先于其他神经病理学特征和认知能力下降。我们以前的研究表明，SFRP1 是一种在临床前阶段就在阿尔茨海默病大脑中升高的神经胶质衍生蛋白，它有助于疾病的进展，这表明神经胶质因素与早期发病机制有关。在这里，我们生成并分析了过表达星形胶质细胞 SFRP1 的转基因小鼠。SFRP1 的积累会导致成年小鼠的早期树突和突触缺陷，随后出现突触长期潜能受损和认知能力下降，只有当动物衰老时才会明显，从而模拟了 AD 在结构和功能上的时间区别。这种表型与蛋白质组学变化相关，包括神经肽等结构性突触蛋白的增加，在培养的海马神经元中，神经肽与 SFRP1 紧密定位。我们的结论是，过量的SFRP1阻碍了突触蛋白的周转，降低了突触的可塑性--这可能是在前驱AD患者大脑中观察到的突触病变的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.