Department of Biology, Western University, London, Canada.
Department of Biology, Indiana University, Bloomington, IN 47405, USA.
Aging (Albany NY). 2023 Feb 28;15(4):947-981. doi: 10.18632/aging.204565.
The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.
星形胶质细胞-神经元乳酸穿梭假说假设，星形胶质细胞产生的乳酸被转运到神经元中，为长期记忆所需的代谢过程提供燃料。尽管脊椎动物的研究表明，乳酸穿梭对于认知功能很重要，但尚不确定这种代谢偶联形式是否在无脊椎动物中保守，或者是否受年龄影响。乳酸脱氢酶（Ldh）是一种限速酶，可将乳酸和丙酮酸相互转化。在这里，我们通过基因操作改变神经元或神经胶质细胞中乳酸脱氢酶（dLdh）的表达，以评估改变乳酸代谢对不同年龄无脊椎动物衰老和长期求偶记忆的影响。我们还评估了生存、负趋地性、大脑中性脂质（脂质滴的核心成分）和大脑代谢物。神经元中 dLdh 的上调和下调均导致随着年龄的增长而生存能力下降和记忆障碍。下调 dLdh 在神经胶质细胞中的表达导致与年龄相关的记忆障碍而不改变生存能力，而上调 dLdh 在神经胶质细胞中的表达降低生存能力而不破坏记忆。神经元和神经胶质细胞中 dLdh 的上调均增加了中性脂质的积累。我们提供的证据表明，随着年龄的增长，乳酸代谢的改变会影响三羧酸（TCA）循环、2-羟基戊二酸（2HG）和中性脂质的积累。总之，我们的研究结果表明，无论是在神经胶质细胞还是神经元中直接改变乳酸代谢都会影响记忆和生存能力，但仅在年龄依赖的方式下。
