McGregor Eric R, Lasky Danny J, Rippentrop Olivia J, Clark Josef P, Wright Samantha, Jones Mathew V, Anderson Rozalyn M
Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI, USA.
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
Commun Biol. 2025 Jan 4;8(1):8. doi: 10.1038/s42003-024-07391-z.
Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation.
脑线粒体代谢变化与功能衰退同时出现；然而，二者之间的直接联系尚未确立。在此，我们表明通过脂联素受体激活剂AdipoRon（AR）靶向线粒体可清除神经原纤维缠结（NFTs）并挽救神经元tau蛋白病相关缺陷。AR通过涉及能量感应激酶AMPK和生长感应激酶GSK3b的机制降低了磷酸化tau蛋白水平并减轻了NFT负担。对AR的转录反应包括广泛的代谢和功能途径。溶酶体途径的诱导涉及LC3和p62的激活，神经元生长的恢复需要应激反应激酶JNK。NFTs对线粒体活性、ATP产生和脂质储存的负面影响得到纠正。电生理指标（如静息电位、电阻、放电模式）的缺陷也得到纠正。这些发现揭示了一个将线粒体功能、细胞维持过程和神经元功能的电学方面联系起来的网络，可通过激活脂联素受体来靶向作用。
