Galactose-replacement unmasks the biochemical consequences of the G11778A mitochondrial DNA mutation of LHON in patient-derived fibroblasts.

Leber's hereditary optic neuropathy (LHON) is a visual impairment associated with mutations of mitochondrial genes encoding elements of the electron transport chain. While much is known about the genetics of LHON, the cellular pathophysiology leading to retinal ganglion cell degeneration and subsequent vision loss is poorly understood. The impacts of the G11778A mutation of LHON on bioenergetics, redox balance and cell proliferation were examined in patient-derived fibroblasts. Replacement of glucose with galactose in the culture media reveals a deficit in the proliferation of G11778A fibroblasts, imparts a reduction in ATP biosynthesis, and a reduction in capacity to accommodate exogenous oxidative stress. While steady-state ROS levels were unaffected by the LHON mutation, cell survival was diminished in response to exogenous H2O2.

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.

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 Drosophila melanogaster 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.

Using the urea cycle to shift astrocytes from harmful to helpful in Alzheimer's disease.

Astrocytes are brain cells that react to Alzheimer's disease pathology in ways that can have either beneficial or detrimental effects. In this issue of Cell Metabolism, Ju et al. outline a novel strategy for coercing astrocytes to a neuroprotective state by maintaining liver-like detoxification in the brain without producing damaging byproducts.

Lactate dehydrogenase expression modulates longevity and neurodegeneration in Drosophila melanogaster.

Lactate dehydrogenase (LDH) catalyzes the conversion of glycolysis-derived pyruvate to lactate. Lactate has been shown to play key roles in brain energetics and memory formation. However, lactate levels are elevated in aging and Alzheimer's disease patients, and it is not clear whether lactate plays protective or detrimental roles in these contexts. Here we show that Ldh transcript levels are elevated and cycle with diurnal rhythm in the heads of aged flies and this is associated with increased LDH protein, enzyme activity, and lactate concentrations. To understand the biological significance of increased Ldh gene expression, we genetically manipulated Ldh levels in adult neurons or glia. Overexpression of Ldh in both cell types caused a significant reduction in lifespan whereas Ldh down-regulation resulted in lifespan extension. Moreover, pan-neuronal overexpression of Ldh disrupted circadian locomotor activity rhythms and significantly increased brain neurodegeneration. In contrast, reduction of Ldh in neurons delayed age-dependent neurodegeneration. Thus, our unbiased genetic approach identified Ldh and lactate as potential modulators of aging and longevity in flies.

Social behavior and aging: A fly model.

The field of behavioral genetics has recently begun to explore the effect of age on social behaviors. Such studies are particularly important, as certain neuropsychiatric disorders with abnormal social interactions, like autism and schizophrenia, have been linked to older parents. Appropriate social interaction can also have a positive impact on longevity, and is associated with successful aging in humans. Currently, there are few genetic models for understanding the effect of aging on social behavior and its potential transgenerational inheritance. The fly is emerging as a powerful model for identifying the basic molecular mechanisms underlying neurological and neuropsychiatric disorders. In this review, we discuss these recent advancements, with a focus on how studies in Drosophila melanogaster have provided insight into the effect of aging on aspects of social behavior, including across generations.

Aerobic Glycolysis Is Required for Spatial Memory Acquisition But Not Memory Retrieval in Mice.

The consolidation of newly formed memories and their retrieval are energetically demanding processes. Aerobic glycolysis (AG), also known as the Warburg effect, consists of the production of lactate from glucose in the presence of oxygen. The astrocyte neuron lactate shuttle hypothesis posits that astrocytes process glucose by AG to generate lactate, which is used as a fuel source within neurons to maintain synaptic activity. Studies in mice have demonstrated that lactate transport between astrocytes and neurons is required for long-term memory formation, yet the role of lactate production in memory acquisition and retrieval has not previously been explored. Here, we examined the effect of dichloroacetate (DCA), a chemical inhibitor of lactate production, on spatial learning and memory in mice using the Morris water maze (MWM). In vivo hyperpolarized 13C-pyruvate magnetic resonance spectroscopy revealed decreased conversion of pyruvate to lactate in the mouse brain following DCA administration, concomitant with a reduction in the phosphorylation of pyruvate dehydrogenase. DCA exposure before each training session in the MWM impaired learning, which subsequently resulted in impaired memory during the probe trial. In contrast, mice that underwent training without DCA exposure, but received a single DCA injection before the probe trial exhibited normal memory. Our findings indicate that AG plays a key role during memory acquisition but is less important for the retrieval of established memories. Thus, the activation of AG may be important for learning-dependent synaptic plasticity rather than the activation of signaling cascades required for memory retrieval.

Simple Protocol for Distinguishing Drug-induced Effects on Spatial Memory Acquisition, Consolidation and Retrieval in Mice Using the Morris Water Maze.

The Morris water maze (MWM) is one of the most commonly used tests for assessing spatial learning and memory in mice. While the MWM is highly amenable to testing the effects of memory modifying drugs, most studies do not consider the timing or duration of drug exposure when conducting the MWM assay; factors that can strongly influence the effect of the drug on different stages of memory and interfere with data interpretation. Herein we describe a MWM protocol which offers the advantage of distinguishing the impact of a fast acting intraperitoneally (IP) injected drug on the different stages of spatial memory: acquisition, consolidation, and retrieval. Mice initially undergo habituation to both the MWM apparatus and IP injection procedure over the course of three days. For assessing the effect of a drug on memory acquisition, mice are injected with the drug prior to training sessions over four consecutive days, where mice learn to find an escape platform in a circular water tank using distal spatial cues. To determine the effect of the drug on memory consolidation, mice are injected with the drug immediately after each training session. For testing the effect of a drug on memory retrieval, mice receive mock IP injections on each training day and the drug is IP injected only once, prior to a probe trial, where mice attempt to locate the platform following its removal from the tank. This protocol provides a simple strategy for distinguishing the effect(s) of a CNS acting drug on the different stages of memory.