MiR Binding Sites, Frontal Lobe Upregulated.

Proper transport of RNAs to synapses is essential for localized translation of proteins in response to synaptic signals and synaptic plasticity. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by accumulation of amyloid aggregates and hyperphosphorylated tau neurofibrillary tangles followed by widespread synapse loss. To understand whether RNA synaptic localization is impacted in AD, we performed RNA sequencing on synaptosomes and brain homogenates from AD patients and cognitively healthy controls. This resulted in the discovery of hundreds of mislocalized mRNAs in AD among frontal and temporal brain regions. Similar observations were found in an APPswe/PSEN1dE9 mouse model. Furthermore, major differences were observed among circular RNAs (circRNAs) localized to synapses in AD including two overlapping isoforms of circGSK3β, one upregulated, and one downregulated. Expression of these distinct isoforms affected tau phosphorylation in neuronal cells substantiating the importance of circRNAs in the brain and pointing to a new class of therapeutic targets.

RNA向突触的精准转运，对于响应突触信号的蛋白质局部翻译以及突触可塑性至关重要。阿尔茨海默病（Alzheimer’s disease, AD）是一类以淀粉样蛋白聚集、过度磷酸化tau蛋白形成神经原纤维缠结为特征的神经退行性疾病，病程进展中会伴随广泛的突触丢失。为探究AD患者体内RNA的突触定位是否受到影响，本研究对阿尔茨海默病患者与认知健康对照者的突触体（synaptosomes）及脑匀浆开展了RNA测序。结果在AD患者的额叶与颞叶脑区中，发现了数百个定位异常的信使RNA（messenger RNA, mRNA）。这一实验现象在APPswe/PSEN1dE9双转基因小鼠模型中得到了重复验证。此外，AD患者突触定位的环状RNA（circular RNAs, circRNAs）亦存在显著差异，例如circGSK3β的两种重叠剪接异构体，其中一种表达上调，另一种则表达下调。进一步研究发现，这些不同异构体的表达会影响神经元细胞内的tau蛋白磷酸化水平，这不仅证实了环状RNA在脑中的重要生物学功能，同时也为新型治疗靶点的开发指明了方向。