Chatterjee Snehajyoti, Bahl Ethan, Mukherjee Utsav, Walsh Emily N, Shetty Mahesh Shivarama, Yan Amy L, Vanrobaeys Yann, Lederman Joseph D, Giese K Peter, Michaelson Jacob, Abel Ted
Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA.
Sci Adv. 2022 Mar 25;8(12):eabm6063. doi: 10.1126/sciadv.abm6063. Epub 2022 Mar 23.
The mechanisms underlying memory loss associated with Alzheimer's disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of genes encoding chaperones that localize to the endoplasmic reticulum (ER). These chaperones fold and traffic plasticity-related proteins to the cell surface during long-lasting forms of synaptic plasticity and memory. Dysregulation of Nr4a transcription factors and ER chaperones is linked to ADRD, and overexpressing Nr4a1 or the chaperone Hspa5 ameliorates long-term memory deficits in a tau-based mouse model of ADRD, pointing toward innovative therapeutic approaches for treating memory loss. Our findings establish a unique molecular concept underlying long-term memory and provide insights into the mechanistic basis of cognitive deficits in dementia.
与阿尔茨海默病及相关痴呆症（ADRD）相关的记忆丧失背后的机制仍不清楚，并且不存在有效的治疗方法。基础研究表明，核受体4a（Nr4a）家族的一组转录调节蛋白充当长期记忆的分子开关。在这里，我们表明Nr4a蛋白调节编码定位于内质网（ER）的伴侣蛋白的基因的转录。在持久形式的突触可塑性和记忆过程中，这些伴侣蛋白将与可塑性相关的蛋白折叠并运输到细胞表面。Nr4a转录因子和内质网伴侣蛋白的失调与ADRD有关，在基于tau的ADRD小鼠模型中过表达Nr4a1或伴侣蛋白Hspa5可改善长期记忆缺陷，这为治疗记忆丧失指明了创新的治疗方法。我们的发现建立了一个独特的长期记忆分子概念，并为痴呆症认知缺陷的机制基础提供了见解。
