Fourriere Lou, Gleeson Paul A
The Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
Front Cell Dev Biol. 2025 Apr 15;13:1550211. doi: 10.3389/fcell.2025.1550211. eCollection 2025.
Alzheimer's disease is a devastating and incurable neurological disease. Most of the current research has focused on developing drugs to clear the extracellular amyloid plaques in the brain of Alzheimer's disease patients. However, this approach is limited as it does not treat the underlying cause of the disease. In this review, we highlight the evidence in the field showing that the accumulation of intracellular toxic amyloid-ß could underpin very early events in neuronal death in both familial early-onset and sporadic late-onset alzheimer's disease. Indeed, intracellular amyloid-ß, which is produced within intracellular compartments, has been shown to perturb endosomal and secretory organelles, in different neuronal models, and the brain of Alzheimer's patients, leading to membrane trafficking defects and perturbation of neuronal function associated with cognition defects. The Golgi apparatus is a central transport and signaling hub at the crossroads of the secretory and endocytic pathways and perturbation of the Golgi ribbon structure is a hallmark of Alzheimer's disease. Here, we discuss the role of the Golgi as a major player in the regulation of amyloid-β production and propose that the Golgi apparatus plays a key role in a cellular network which can seed the onset of Alzheimer's disease. Moreover, we propose that the Golgi is central in an intracellular feedback loop leading to an enhanced level of amyloid-β production resulting in early neuronal defects before the appearance of clinical symptoms. Further advances in defining the molecular pathways of this intracellular feedback loop could support the design of new therapeutic strategies to target a primary source of neuronal toxicity in this disease.
阿尔茨海默病是一种毁灭性的、无法治愈的神经疾病。目前大多数研究都集中在开发药物以清除阿尔茨海默病患者大脑中的细胞外淀粉样斑块。然而，这种方法存在局限性，因为它并未针对该疾病的根本病因进行治疗。在这篇综述中，我们强调该领域的证据表明，细胞内有毒淀粉样β蛋白的积累可能是家族性早发型和散发性晚发型阿尔茨海默病神经元死亡早期事件的基础。事实上，在细胞内区室中产生的细胞内淀粉样β蛋白，已被证实在不同的神经元模型以及阿尔茨海默病患者的大脑中会扰乱内体和分泌细胞器，导致膜运输缺陷以及与认知缺陷相关的神经元功能紊乱。高尔基体是分泌和内吞途径交汇点上的一个中央运输和信号枢纽，高尔基体带结构的紊乱是阿尔茨海默病的一个标志。在此，我们讨论高尔基体作为淀粉样β蛋白产生调控中的主要参与者的作用，并提出高尔基体在一个可能引发阿尔茨海默病发病的细胞网络中起关键作用。此外，我们提出高尔基体在一个细胞内反馈回路中起核心作用，该回路导致淀粉样β蛋白产生水平升高，从而在临床症状出现之前就导致早期神经元缺陷。在确定这个细胞内反馈回路的分子途径方面取得进一步进展，可能有助于设计新的治疗策略，以针对该疾病中神经元毒性的主要来源。
