Harris Richard A, Tindale Lauren, Lone Asad, Singh Olivia, Macauley Shannon L, Stanley Molly, Holtzman David M, Bartha Robert, Cumming Robert C
Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada.
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, and.
J Neurosci. 2016 Feb 10;36(6):1871-8. doi: 10.1523/JNEUROSCI.3131-15.2016.
Aerobic glycolysis and lactate production in the brain plays a key role in memory, yet the role of this metabolism in the cognitive decline associated with Alzheimer's disease (AD) remains poorly understood. Here we examined the relationship between cerebral lactate levels and memory performance in an APP/PS1 mouse model of AD, which progressively accumulates amyloid-β. In vivo (1)H-magnetic resonance spectroscopy revealed an age-dependent decline in lactate levels within the frontal cortex of control mice, whereas lactate levels remained unaltered in APP/PS1 mice from 3 to 12 months of age. Analysis of hippocampal interstitial fluid by in vivo microdialysis revealed a significant elevation in lactate levels in APP/PS1 mice relative to control mice at 12 months of age. An age-dependent decline in the levels of key aerobic glycolysis enzymes and a concomitant increase in lactate transporter expression was detected in control mice. Increased expression of lactate-producing enzymes correlated with improved memory in control mice. Interestingly, in APP/PS1 mice the opposite effect was detected. In these mice, increased expression of lactate producing enzymes correlated with poorer memory performance. Immunofluorescent staining revealed localization of the aerobic glycolysis enzymes pyruvate dehydrogenase kinase and lactate dehydrogenase A within cortical and hippocampal neurons in control mice, as well as within astrocytes surrounding amyloid plaques in APP/PS1 mice. These observations collectively indicate that production of lactate, via aerobic glycolysis, is beneficial for memory function during normal aging. However, elevated lactate levels in APP/PS1 mice indicate perturbed lactate processing, a factor that may contribute to cognitive decline in AD.
Lactate has recently emerged as a key metabolite necessary for memory consolidation. Lactate is the end product of aerobic glycolysis, a unique form of metabolism that occurs within certain regions of the brain. Here we detected an age-dependent decline in the expression of aerobic glycolysis enzymes and a concomitant decrease in lactate levels within the frontal cortex of wild-type mice. Improved memory performance in wild-type mice correlated with elevated expression of aerobic glycolysis enzymes. Surprisingly, lactate levels remained elevated with age and increased aerobic glycolysis enzyme expression correlated with poorer memory performance in APP/PS1 mice. These findings suggest that while lactate production is beneficial for memory in the healthy aging brain, it might be detrimental in an Alzheimer's disease context.
大脑中的有氧糖酵解和乳酸生成在记忆中起关键作用，然而这种代谢在与阿尔茨海默病（AD）相关的认知衰退中的作用仍知之甚少。在此，我们在APP/PS1小鼠AD模型中研究了脑乳酸水平与记忆表现之间的关系，该模型会逐渐积累β-淀粉样蛋白。体内氢磁共振波谱显示，对照小鼠额叶皮质中的乳酸水平随年龄下降，而3至12月龄的APP/PS1小鼠的乳酸水平保持不变。通过体内微透析分析海马间质液发现，12月龄时，APP/PS1小鼠的乳酸水平相对于对照小鼠显著升高。在对照小鼠中检测到关键有氧糖酵解酶水平随年龄下降，同时乳酸转运蛋白表达增加。对照小鼠中乳酸生成酶表达增加与记忆改善相关。有趣的是，在APP/PS1小鼠中检测到相反的效果。在这些小鼠中，乳酸生成酶表达增加与较差的记忆表现相关。免疫荧光染色显示，对照小鼠的皮质和海马神经元内以及APP/PS1小鼠淀粉样斑块周围的星形胶质细胞内存在有氧糖酵解酶丙酮酸脱氢酶激酶和乳酸脱氢酶A。这些观察结果共同表明，通过有氧糖酵解产生乳酸对正常衰老过程中的记忆功能有益。然而，APP/PS1小鼠中升高的乳酸水平表明乳酸处理受到干扰，这可能是导致AD认知衰退的一个因素。
乳酸最近已成为记忆巩固所必需的关键代谢物。乳酸是有氧糖酵解的终产物，有氧糖酵解是一种在大脑特定区域发生的独特代谢形式。在此，我们检测到野生型小鼠额叶皮质中，有氧糖酵解酶表达随年龄下降，同时乳酸水平降低。野生型小鼠记忆表现的改善与有氧糖酵解酶表达升高相关。令人惊讶的是，APP/PS1小鼠中乳酸水平随年龄升高，且有氧糖酵解酶表达增加与较差的记忆表现相关。这些发现表明，虽然乳酸生成对健康衰老大脑中的记忆有益，但在阿尔茨海默病背景下可能有害。
