School of Pharmacy and Biomolecular Sciences, University of Brighton, UK.
Drug Development, Department of Physiology, School of Medicine, Trinity College Dublin, Ireland.
FEBS Open Bio. 2021 Jan;11(1):146-163. doi: 10.1002/2211-5463.13036. Epub 2020 Dec 1.
In the brain, REST (Repressor Element-1 Silencing Transcription factor) is a key regulator of neuron cell-specific gene expression. Nuclear translocation of neuronal REST has been shown to be neuroprotective in a healthy ageing context. In contrast, inability to upregulate nuclear REST is thought to leave ageing neurons vulnerable to neurodegenerative stimuli, such as Alzheimer's disease (AD) pathology. Hippocampal and cortical neurons are known to be particularly susceptible to AD-associated neurodegeneration. However, REST expression has not been extensively characterised in the healthy ageing brain. Here, we examined the spatiotemporal immunolocalisation of REST in the brains of healthy ageing wild-type Fischer-344 and transgenic Alzheimer's disease rats (TgF344-AD). Nuclear expression of REST increased from 6 months to 18 months of age in the hippocampus, frontal cortex and subiculum of wild-type rats, but not in TgF344-AD rats. No changes in REST were measured in more posterior cortical regions or in the thalamus. Interestingly, levels of the presynaptic marker synaptophysin, a known gene target of REST, were lower in CA1 hippocampal neurons of 18-month TgF344-AD rats compared to 18-month wild-types, suggesting that elevated nuclear REST may protect against synapse loss in the CA1 of 18-month wild-type rats. High REST expression in ageing wild-type rats did not, however, protect against axonal loss nor against astroglial reactivity in the hippocampus. Taken together, our data confirm that changes in nuclear REST expression are context-, age- and brain region-specific. Moreover, key brain structures involved in learning and memory display elevated REST expression in healthy ageing wild-type rats but not TgF344-AD rats.
在大脑中，REST（Repressor Element-1 Silencing Transcription factor）是神经元细胞特异性基因表达的关键调节剂。已有研究表明，神经元 REST 的核转位在健康衰老背景下具有神经保护作用。相比之下，核内 REST 上调能力的丧失被认为使衰老神经元易受神经退行性刺激的影响，如阿尔茨海默病（AD）病理。海马体和皮质神经元被认为特别容易受到 AD 相关神经退行性变的影响。然而，REST 的表达在健康衰老的大脑中尚未得到广泛研究。在这里，我们研究了健康衰老的野生型 Fischer-344 大鼠和转基因 AD 大鼠（TgF344-AD）大脑中 REST 的时空免疫定位。野生型大鼠的海马体、额皮质和下托区的 REST 核表达从 6 个月增加到 18 个月，但 TgF344-AD 大鼠中没有变化。在更靠后的皮质区域或丘脑没有测量到 REST 的变化。有趣的是，18 个月的 TgF344-AD 大鼠 CA1 海马神经元中突触前标志物突触素的水平低于 18 个月的野生型大鼠，这表明升高的核内 REST 可能有助于保护 18 个月野生型大鼠 CA1 中的突触丢失。然而，衰老野生型大鼠中高 REST 表达并不能防止轴突丢失，也不能防止海马体中的星形胶质细胞反应。总之，我们的数据证实了核内 REST 表达的变化具有上下文、年龄和脑区特异性。此外，参与学习和记忆的关键大脑结构在健康衰老的野生型大鼠中显示出升高的 REST 表达，但在 TgF344-AD 大鼠中则没有。
