Yeates Catherine, Deshpande Prajakta, Kango-Singh Madhuri, Singh Amit
Department of Biology, University of Dayton, Dayton, OH, USA.
Department of Biology; Premedical Program; The Integrative Science and Engineering Center, University of Dayton, Dayton, OH, USA.
Neural Regen Res. 2023 Apr;18(4):784-789. doi: 10.4103/1673-5374.354516.
The pathology of Alzheimer's disease involves a long preclinical period, where the characteristic clinical symptoms of the changes in the brain are undetectable. During the preclinical period, homeostatic mechanisms may help prevent widespread cell death. Evidence has pointed towards selective cell death of diseased neurons playing a potentially protective role. As the disease progresses, dysregulation of signaling pathways that govern cell death contributes to neurodegeneration. Aberrant activation of the c-Jun N-terminal kinase pathway has been established in human and animal models of Alzheimer's disease caused by amyloid-beta 42- or tau-mediated neurodegeneration. Clonal mosaic studies in Drosophila that examine amyloid-beta 42 in a subset of neurons suggest complex interplay between amyloid-beta 42-expressing and wild-type cells. This review examines the role of c-Jun N-terminal kinase signaling in the context of cell competition and short-range signaling interactions between amyloid-beta 42-expressing and wild-type neurons. Cell competition is a conserved phenomenon regulating tissue integrity by assessing the fitness of cells relative to their neighbors and eliminating suboptimal cells. Somatic clones of amyloid-beta 42 that juxtapose genetically distinct neuronal cell populations show promise for studying neurodegeneration. Generating genetic mosaics with labeled clones of amyloid-beta 42- or tau-expressing and wild-type neurons will allow us to understand how short-range signaling alterations trigger cell death in neurons and thereby contribute to the progression of Alzheimer's disease. These approaches have the potential to uncover biomarkers for early Alzheimer's disease detection and new therapeutic targets for intervention.
阿尔茨海默病的病理学涉及一个漫长的临床前期，在此期间大脑变化的特征性临床症状无法检测到。在临床前期，体内平衡机制可能有助于防止广泛的细胞死亡。有证据表明，患病神经元的选择性细胞死亡可能起到保护作用。随着疾病进展，控制细胞死亡的信号通路失调会导致神经退行性变。在由β-淀粉样蛋白42或tau介导的神经退行性变引起的阿尔茨海默病的人类和动物模型中，已证实c-Jun氨基末端激酶通路的异常激活。在果蝇中对一部分神经元中的β-淀粉样蛋白42进行的克隆镶嵌研究表明，表达β-淀粉样蛋白42的细胞与野生型细胞之间存在复杂的相互作用。本综述探讨了c-Jun氨基末端激酶信号在细胞竞争以及表达β-淀粉样蛋白42的神经元与野生型神经元之间的短程信号相互作用中的作用。细胞竞争是一种保守现象，通过评估细胞相对于其邻居的适应性并清除次优细胞来调节组织完整性。与基因不同的神经元细胞群体并列的β-淀粉样蛋白42的体细胞克隆有望用于研究神经退行性变。生成带有表达β-淀粉样蛋白42或tau的标记克隆以及野生型神经元的基因镶嵌体，将使我们能够了解短程信号改变如何触发神经元细胞死亡，从而促进阿尔茨海默病的进展。这些方法有可能发现用于早期阿尔茨海默病检测的生物标志物以及新的干预治疗靶点。
