A decrease in energy metabolism is associated with Alzheimer's disease (AD), but it is not known whether the observed decrease exacerbates or protects against the disease. The importance of energy metabolism in AD is reinforced by the observation that variants of dihydrolipoamide dehydrogenase (DLD), is genetically linked to late-onset AD. To determine whether DLD is a suitable therapeutic target, we suppressed the dld-1 gene in Caenorhabditis elegans that express human Aβ peptide in either muscles or neurons. Suppression of the dld-1 gene resulted in significant restoration of vitality and function that had been degraded by Aβ pathology. This included protection of neurons and muscles cells. The observed decrease in proteotoxicity was associated with a decrease in the formation of toxic oligomers rather than a decrease in the abundance of the Aβ peptide. The mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), which like dld-1 gene expression inhibits ATP synthesis, had no significant effect on Aβ toxicity. Proteomics data analysis revealed that beneficial effects after dld-1 suppression could be due to change in energy metabolism and activation of the pathways associated with proteasomal degradation, improved cell signaling and longevity. Thus, some features unique to dld-1 gene suppression are responsible for the therapeutic benefit. By direct genetic intervention, we have shown that acute inhibition of dld-1 gene function may be therapeutically beneficial. This result supports the hypothesis that lowering energy metabolism protects against Aβ pathogenicity and that DLD warrants further investigation as a therapeutic target.

能量代谢的减少与阿尔茨海默病（AD）有关，但尚不清楚观察到的能量代谢减少是否会加剧或预防该疾病。二氢硫辛酰胺脱氢酶 (DLD) 变体与迟发性 AD 存在遗传相关性，这一观察结果强化了能量代谢在 AD 中的重要性。为了确定 DLD 是否是合适的治疗靶点，我们抑制了秀丽隐杆线虫中的dld-1基因，该基因在肌肉或神经元中表达人类 Aβ 肽。抑制dld-1基因可显着恢复因 Aβ 病理学而退化的活力和功能。这包括保护神经元和肌肉细胞。观察到的蛋白质毒性的降低与有毒寡聚体形成的减少有关，而不是与 Aβ 肽丰度的减少有关。线粒体解偶联剂羰基氰化物 4-(三氟甲氧基)苯腙 (FCCP) 与dld-1基因表达一样抑制 ATP 合成，但对 Aβ 毒性没有显着影响。蛋白质组学数据分析显示，抑制dld-1后的有益效果可能是由于能量代谢的变化以及与蛋白酶体降解相关途径的激活、细胞信号传导的改善和寿命的延长。因此， dld-1基因抑制的一些独特特征是产生治疗效果的原因。通过直接基因干预，我们已经证明，急性抑制dld-1基因功能可能具有治疗益处。这一结果支持了这样的假设：降低能量代谢可以防止 Aβ 致病性，并且 DLD 值得作为治疗靶点进行进一步研究。