Department of Neuroscience, Columbia University Medical Center New York, New York, NY, USA.
Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY, USA.
Nat Commun. 2022 Aug 1;13(1):4444. doi: 10.1038/s41467-022-32130-5.
During the early stages of Alzheimer's disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APP knockin human ES cell line. We demonstrate that Aβ42o-dependent over-activation of the CAMKK2-AMPK kinase dyad mediates synaptic loss through coordinated phosphorylation of MFF-dependent mitochondrial fission and ULK2-dependent mitophagy. Our results uncover a unifying stress-response pathway causally linking Aβ42o-dependent structural remodeling of dendritic mitochondria to synaptic loss.
在阿尔茨海默病（AD）的早期阶段，无论是在小鼠模型还是人类患者中，可溶性的β淀粉样蛋白 1-42 寡聚体（Aβ42o）都会在形成不溶性淀粉样斑块之前引发皮质和海马锥体神经元（PNs）中兴奋性突触的丧失（突触毒性）。在转基因 AD 小鼠模型中，我们观察到 CA1 PNs 树突棘顶区的线粒体结构在空间上受到限制的重塑，这与体内最早检测到的突触丧失的树突域相对应。我们还观察到 AMPK 的过度激活，以及源自新的 APP 敲入人 ES 细胞系的 Ngn2 诱导神经元中线粒体生物量的碎片化和丧失增加。我们证明，Aβ42o 依赖性 CAMKK2-AMPK 激酶二聚体的过度激活通过协调 MFF 依赖性线粒体分裂和 ULK2 依赖性线粒体自噬的磷酸化介导突触丧失。我们的研究结果揭示了一种统一的应激反应途径，将 Aβ42o 依赖性树突状线粒体结构重塑与突触丧失联系起来。
