Astrocytes provide crucial support for neurons, contributing to synaptogenesis, synaptic maintenance, and neurotransmitter recycling. Under pathological conditions, deregulation of astrocytes contributes to neurodegenerative diseases such as Alzheimer’s disease (AD). While most research in this field has focused on protein-coding genes, non-coding RNAs, particularly long non-coding RNAs (lncRNAs), have emerged as significant regulatory molecules. In this study, we identified the lncRNA PRDM16-DT as highly enriched in the human brain, where it is almost exclusively expressed in astrocytes. PRDM16-DT and its murine homolog, Prdm16os, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown of PRDM16-DT and Prdm16os revealed its critical role in maintaining astrocyte homeostasis and supporting neuronal function by regulating genes essential for glutamate uptake, lactate release, and neuronal spine density through interactions with the RE1-Silencing Transcription factor (Rest) and Polycomb Repressive Complex 2 (PRC2). Notably, CRISPR-mediated overexpression of Prdm16os mitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance of PRDM16-DT in astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction.

星形胶质细胞为神经元提供重要支持，有助于突触发生、突触维持和神经递质回收。在病理条件下，星形胶质细胞的失调会导致阿尔茨海默病（AD）等神经退行性疾病。虽然该领域的大多数研究都集中在蛋白质编码基因上，但非编码 RNA，特别是长非编码 RNA (lncRNA)，已成为重要的调控分子。在这项研究中，我们发现 lncRNA PRDM16-DT在人脑中高度富集，几乎只在星形胶质细胞中表达。 PRDM16-DT及其小鼠同源物Prdm16os在 AD 患者和 AD 模型的大脑中表达下调。与此相一致的是， PRDM16-DT和Prdm16os的敲除揭示了其在维持星形胶质细胞稳态和支持神经元功能方面的关键作用，通过与RE1沉默转录因子（Rest）相互作用来调节谷氨酸摄取、乳酸释放和神经元棘密度所必需的基因。 ) 和 Polycomb 抑制复合体 2 (PRC2)。值得注意的是，CRISPR 介导的Prdm16os过度表达减轻了与 AD 发病机制相关的刺激诱导的星形胶质细胞的功能缺陷。这些发现强调了PRDM16-DT在星形胶质细胞功能中的重要性及其作为以星形胶质细胞功能障碍为特征的神经退行性疾病的新型治疗靶点的潜力。