Hippocampal Adult Neurogenesis Is Maintained by Neil3-Dependent Repair of Oxidative DNA Lesions in Neural Progenitor Cells

SummaryAccumulation of oxidative DNA damage has been proposed as a potential cause of age-related cognitive decline. The major pathway for removal of oxidative DNA base lesions is base excision repair, which is initiated by DNA glycosylases. In mice, Neil3 is the main DNA glycosylase for repair of hydantoin lesions in single-stranded DNA of neural stem/progenitor cells, promoting neurogenesis. Adult neurogenesis is crucial for maintenance of hippocampus-dependent functions involved in behavior. Herein, behavioral studies reveal learning and memory deficits and reduced anxiety-like behavior in Neil3−/− mice. Neural stem/progenitor cells from aged Neil3−/− mice show impaired proliferative capacity and reduced DNA repair activity. Furthermore, hippocampal neurons in Neil3−/− mice display synaptic irregularities. It appears that Neil3-dependent repair of oxidative DNA damage in neural stem/progenitor cells is required for maintenance of adult neurogenesis to counteract the age-associated deterioration of cognitive performance

Molecular anatomy of adult mouse leptomeninges.

Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Lactate transport and receptor actions in cerebral malaria

Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolised mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood-brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM

Is lactate a Volume Transmitter of Metabolic States of the Brain?

We present the perspective that lactate is a volume transmitter of cellular signals in brain that acutely and chronically regulate the energy metabolism of large neuronal ensembles. From this perspective, we interpret recent evidence to mean that lactate transmission serves the maintenance of network metabolism by two different mechanisms, one by regulating the formation of cAMP via the lactate receptor GPR81, the other by adjusting the NADH/NAD+ redox ratios, both linked to the maintenance of brain energy turnover and possibly cerebral blood flow. The roles of lactate as mediator of metabolic information rather than metabolic substrate answer a number of questions raised by the controversial oxidativeness of astrocytic metabolism and its contribution to neuronal function

Oxygen consumption and blood flow coupling in human motor cortex during intense finger tapping:implication for a role of lactate

Rates of cerebral blood flow (CBF) and glucose consumption (CMR(glc)) rise in cerebral cortex during continuous stimulation, while the oxygen-glucose index (OGI) declines as an index of mismatched coupling of oxygen consumption (cerebral metabolic rate of oxygen—CMRO(2)) to CBF and CMR(glc). To test whether the mismatch reflects a specific role of aerobic glycolysis during functional brain activation, we determined CBF and CMRO(2) with positron emission tomography (PET) when 12 healthy volunteers executed finger-to-thumb apposition of the right hand. Movements began 1, 10, or 20 minutes before administration of the radiotracers. In primary and supplementary motor cortices and cerebellum, CBF had increased at 1 minute of exercise and remained elevated for the duration of the 20-minute session. In contrast, the CMRO(2) numerically had increased insignificantly in left M1 and supplementary motor area at 1 minute, but had declined significantly at 10 minutes, returning to baseline at 20 minutes. As measures of CMR(glc) are impossible during short-term activations, we used measurements of CBF as indices of CMR(glc). The decline of CMRO(2) at 10 minutes paralleled a calculated decrease of OGI at this time. The implied generation of lactate in the tissue suggested an important hypothetical role of the metabolite as regulator of CBF during activation