Mary Arnaud, Barale Samantha, Eysert Fanny, Valverde Audrey, Lacas-Gervais Sandra, Bauer Charlotte, Eddarkaoui Sabiha, Buée Luc, Buée-Scherrer Valérie, Checler Frédéric, Chami Mounia
Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, Valbonne, 06560, France.
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Avenue du Swing 6, Belvaux, L-4367, Luxembourg.
Alzheimers Res Ther. 2025 Jun 2;17(1):127. doi: 10.1186/s13195-025-01772-0.
The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key cellular signaling node, the alteration of which likely contribute to AD development. This study investigated the AMPK-ULK1 pathway activation state in AD and the impact of its modulation on mitochondria structure and function as well as on AD-related alterations. We show in human sporadic AD and 3xTgAD mice brains a defective activating phosphorylation of ULK1 despite the active phosphorylation of AMPK. In addition, we reported defective p-AMPK and p-ULK1 in cells expressing the amyloid precursor protein with the familial Swedish mutation. We then show that the antidiabetic metformin (Met) drug-mediated AMPK-ULK1 cascade activation alleviates structural and functional mitochondrial abnormalities in AD cells and mice brains. Furthermore, in the 3xTgAD brains, it reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as amyloid beta (Aβ) burden, microgliosis and astrogliosis occurring at a later disease stage. AMPK-ULK1 activation increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartments and the recruitment of Iba1 cells to Aβ plaques in vivo and enhances cathepsin D activity and phagocytic activity of microglia in vitro. Additionally, AMPK-ULK1 activation normalizes dendritic spine morphology in organotypic hippocampal slice cultures modeling AD and alleviates learning deficit in symptomatic 3xTgAD mice. Our study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.
单磷酸腺苷激活的蛋白激酶（AMPK）及其下游效应物Unc-51样自噬激活激酶1（ULK1）代表一个关键的细胞信号节点，其改变可能促成阿尔茨海默病（AD）的发展。本研究调查了AD中AMPK-ULK1通路的激活状态及其调节对线粒体结构和功能以及AD相关改变的影响。我们发现在人类散发性AD和3xTgAD小鼠大脑中，尽管AMPK发生了活性磷酸化，但ULK1的激活磷酸化存在缺陷。此外，我们报道在表达具有家族性瑞典突变的淀粉样前体蛋白的细胞中，p-AMPK和p-ULK1存在缺陷。然后我们表明，抗糖尿病药物二甲双胍（Met）介导的AMPK-ULK1级联激活可减轻AD细胞和小鼠大脑中线粒体的结构和功能异常。此外，在3xTgAD大脑中，它减少了APP C末端片段（APP-CTFs）的早期积累以及在疾病后期出现的淀粉样β（Aβ）负担、小胶质细胞增生和星形胶质细胞增生。AMPK-ULK1激活增加了APP-CTFs在组织蛋白酶D阳性溶酶体区室中的定位以及体内Iba1细胞向Aβ斑块的募集，并增强了体外小胶质细胞的组织蛋白酶D活性和吞噬活性。此外，AMPK-ULK1激活使模拟AD的器官型海马切片培养物中的树突棘形态正常化，并减轻了有症状的3xTgAD小鼠的学习缺陷。我们的研究证明了靶向AMPK-ULK1级联以逆转早期和晚期AD相关改变的潜在治疗益处，值得在基础研究和人类临床研究中进一步探讨。
