PDF(Pubmed)
Abstract：
Impaired brain glucose metabolism is an early indicator of Alzheimer\'s disease (AD); however, the fundamental mechanism is unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3β (IDH3β) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice\'s brains. Further investigations demonstrated that the knockdown of IDH3β induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3β, the elevated PAX6 in turn inhibited the expression of IDH3β, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3β and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β. Breaking this loop by upregulating IDH3β or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.
摘要：
脑葡萄糖代谢受损是阿尔茨海默病(AD)的早期指标;然而,根本机制未知。在这项研究中,我们发现异柠檬酸脱氢酶3β（IDH3β）水平大幅下降，一种关键的三羧酸循环酶，在AD患者和AD转基因小鼠的大脑中。进一步的研究表明，IDH3β的敲低诱导氧化-磷酸化解偶联，导致能量代谢和乳酸积累减少。由此增加的乳酸，乳酰的来源，被发现促进组蛋白的乳酸化，从而增强配对盒基因6(PAX6)的表达。作为IDH3β的抑制性转录因子，PAX6的升高又抑制了IDH3β的表达，导致tau过度磷酸化，突触损伤,学习和记忆缺陷类似于AD。在AD转基因小鼠中，发现上调IDH3β和下调PAX6可改善认知功能并逆转AD样病变。总的来说，我们的数据表明,受损的氧化磷酸化通过IDH3β-乳酸-PAX6-IDH3β的正反馈抑制回路加速AD进展.通过上调IDH3β或下调PAX6来打破该循环可减轻AD神经变性和认知损害。
