Barshop Institute for Longevity and Aging Studies, San Antonio, TX, United States; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, United States; Department of Cell Systems and Anatomy, San Antonio, TX, United States; University of Texas Health San Antonio, San Antonio, TX, United States.
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA, United States.
Neuroscience. 2023 May 10;518:101-111. doi: 10.1016/j.neuroscience.2022.04.017. Epub 2022 Apr 27.
Alzheimer's disease and other tauopathies are neurodegenerative disorders pathologically defined by aggregated forms of tau protein in the brain. While synaptic degradation is a well-established feature of tau-induced neurotoxicity, the underlying mechanisms of how pathogenic forms of tau drive synaptic dysfunction are incompletely understood. Synaptic function and subsequent memory consolidation are dependent upon synaptic plasticity, the ability of synapses to adjust their structure and strength in response to changes in activity. The activity regulated cytoskeleton associated protein ARC acts in the nucleus and at postsynaptic densities to regulate various forms of synaptic plasticity. ARC harbors a retrovirus-like Gag domain that facilitates ARC multimerization and capsid formation. Trans-synaptic transfer of RNA-containing ARC capsids is required for synaptic plasticity. While ARC is elevated in brains of patients with Alzheimer's disease and genetic variants in ARC increase susceptibility to Alzheimer's disease, mechanistic insight into the role of ARC in Alzheimer's disease is lacking. Using a Drosophila model of tauopathy, we find that pathogenic tau significantly increases multimeric species of the protein encoded by the Drosophila homolog of ARC, Arc1, in the adult fly brain. We find that Arc1 is elevated within nuclei and the neuropil of tau transgenic Drosophila, but does not localize to synaptic vesicles or presynaptic terminals. Lastly, we find that genetic manipulation of Arc1 modifies tau-induced neurotoxicity, suggesting that tau-induced Arc1 elevation mediates neurodegeneration. Taken together, our results suggest that ARC elevation in human Alzheimer's disease is a consequence of tau pathology and is a causal factor contributing to neuronal death.
阿尔茨海默病和其他 tau 病是神经退行性疾病，其病理特征是大脑中 tau 蛋白的聚集形式。虽然突触降解是 tau 诱导的神经毒性的一个既定特征，但导致 tau 引起的突触功能障碍的潜在机制尚不完全清楚。突触功能和随后的记忆巩固依赖于突触可塑性，即突触根据活性变化调整其结构和强度的能力。活性调节细胞骨架相关蛋白 ARC 在核内和突触后密度处发挥作用，以调节各种形式的突触可塑性。ARC 具有类似于逆转录病毒的 Gag 结构域，该结构域促进 ARC 多聚化和衣壳形成。包含 RNA 的 ARC 衣壳的突触间转移对于突触可塑性是必需的。虽然 ARC 在阿尔茨海默病患者的大脑中升高，并且 ARC 的遗传变异增加了对阿尔茨海默病的易感性，但对 ARC 在阿尔茨海默病中的作用的机制理解仍然缺乏。使用 tau 病的果蝇模型，我们发现致病性 tau 显著增加了果蝇 ARC 同源物编码的蛋白质的多聚体物种，在成年果蝇大脑中。我们发现 Arc1 在 tau 转基因果蝇的核内和神经突内升高，但不定位到突触小泡或突触前末端。最后，我们发现 Arc1 的遗传操作改变了 tau 诱导的神经毒性，表明 tau 诱导的 Arc1 升高介导了神经退行性变。总之，我们的结果表明，人类阿尔茨海默病中 ARC 的升高是 tau 病理学的结果，是导致神经元死亡的因果因素。
