Search

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging. [ABSTRACT FROM AUTHOR]

Frode Fonnum, a highly respected neuroscientist and toxicologist, has passed away at the age of 86. He was known for his groundbreaking research on neurotransmitters in the brain, particularly GABA and glutamate. Fonnum also played a crucial role in developing protective equipment against chemical weapons and studying environmental toxins. He was widely admired for his intellect, sense of humor, and supportiveness, and his wife, Marit Fonnum, was recognized for her unwavering support throughout his career. Fonnum's contributions to the field will be remembered and appreciated by colleagues worldwide. [Extracted from the article]

Vesicular glutamate transporters (VGLUTs) 1 and 2 show a mutually exclusive distribution in the adult brain that suggests specialization for synapses with different properties of release. Consistent with this distribution, inactivation of the VGLUT1 gene silenced a subset of excitatory neurons in the adult. However, the same cell populations exhibited VGLUT1-independent transmission early in life. Developing hippocampal neurons transiently coexpressed VGLUT2 and VGLUT1 at distinct synaptic sites with different short-term plasticity. The loss of VGLUT1 also reduced the reserve pool of synaptic vesicles. Thus, VGLUT1 plays an unanticipated role in membrane trafficking at the nerve terminal, Synaptic vesicles actively accumulate the principal excitatory neurotransmitter, glutamate (1, 2), enabling its regulated release by exocytosis. A distinct family of proteins implicated in glutamate release by genetic studies in [...]

Aim: Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular‐subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular‐subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1‐dependent effects on neurogenesis in the two main neurogenic niches. Methods: Wild‐type and HCA1 knock‐out mice received high intensity interval exercise, subcutaneous injections of L‐lactate, or saline injections, five days per week for seven weeks. Well‐established markers for proliferating cells (Ki‐67) and immature neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular‐subventricular zone. Results: We demonstrated that neurogenesis in the ventricular‐subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild‐type, but not in HCA1 knock‐out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment. Conclusion: Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular‐subventricular zone was neurogenesis induced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age‐related cognitive decline. [ABSTRACT FROM AUTHOR]

Lactate treatment has shown a therapeutic potential for several neurological diseases, including Alzheimer's disease. In order to optimize the administration of lactate for studies in mouse models, we compared blood lactate dynamics after intraperitoneal (IP) and subcutaneous (SC) injections. We used the 5xFAD mouse model for familial Alzheimer's disease and performed the experiments in both awake and anaesthetized mice. Blood glucose was used as an indication of the hepatic conversion of lactate. In awake mice, both injection routes resulted in high blood lactate levels, mimicking levels reached during high-intensity training. In anaesthetized mice, SC injections resulted in significantly lower lactate levels compared to IP injections. Interestingly, we observed that awake males had significantly higher lactate levels than awake females, while the opposite sex difference was observed during anaesthesia. We did not find any significant difference between transgenic and wild-type mice and therefore believe that our results can be generalized to other mouse models. These results should be considered when planning experiments using lactate treatment in mice. [ABSTRACT FROM AUTHOR]

Both human and animal studies have shown mitochondrial and contractile dysfunction in hearts of type 2 diabetes mellitus (T2DM). Exercise training has shown positive effects on cardiac function, but its effect on the mitochondria have been insufficiently explored. The aim of this study was to assess the effect of exercise training on mitochondrial function in T2DM hearts. We divided T2DM mice (db/db) into a sedentary and an interval training group at 8 weeks of age and used heterozygote db/+ as controls. After 8 weeks of training, we evaluated mitochondrial structure and function, as well as the levels of mRNA and proteins involved in key metabolic processes from the left ventricle. db/db animals showed decreased oxidative phosphorylation capacity and fragmented mitochondria. Mitochondrial respiration showed a blunted response to Ca2+ along with reduced protein levels of the mitochondrial calcium uniporter. Exercise training ameliorated the reduced oxidative phosphorylation in complex (C) I + II, CII and CIV, but not CI or Ca2+ response. Mitochondrial fragmentation was partially restored. mRNA levels of isocitrate, succinate and oxoglutarate dehydrogenase were increased in db/db mice and normalized by exercise training. Exercise training induced an upregulation of two transcripts of peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1α1 and PGC1α4) previously linked to endurance training adaptations and strength training adaptations, respectively. The T2DM heart showed mitochondrial dysfunction at multiple levels and exercise training ameliorated some, but not all mitochondrial dysfunctions. [ABSTRACT FROM AUTHOR]

To date there is no cure available for dementia, and the field calls for novel therapeutic targets. A rapidly growing body of literature suggests that regular endurance training and high cardiorespiratory fitness attenuate cognitive impairment and reduce dementia risk. Such benefits have recently been linked to systemic neurotrophic factors induced by exercise. These circulating biomolecules may cross the blood-brain barrier and potentially protect against neurodegenerative disorders such as Alzheimer's disease. Identifying exercise-induced systemic neurotrophic factors with beneficial effects on the brain may lead to novel molecular targets for maintaining cognitive function and preventing neurodegeneration. Here we review the recent literature on potential systemic mediators of neuroprotection induced by exercise. We focus on the body of translational research in the field, integrating knowledge from the molecular level, animal models, clinical and epidemiological studies. Taken together, the current literature provides initial evidence that exercise-induced, blood-borne biomolecules, such as BDNF and FNDC5/irisin, may be powerful agents mediating the benefits of exercise on cognitive function and may form the basis for new therapeutic strategies to better prevent and treat dementia. [ABSTRACT FROM AUTHOR]

Besides being a neuronal fuel, L-lactate is also a signal in the brain. Whether extracellular L-lactate affects brain metabolism, in particular astrocytes, abundant neuroglial cells, which produce L-lactate in aerobic glycolysis, is unclear. Recent studies suggested that astrocytes express low levels of the L-lactate GPR81 receptor (EC50 ≈ 5 mM) that is in fat cells part of an autocrine loop, in which the Gi-protein mediates reduction of cytosolic cyclic adenosine monophosphate (cAMP). To study whether a similar signaling loop is present in astrocytes, affecting aerobic glycolysis, we measured the cytosolic levels of cAMP, D-glucose and L-lactate in single astrocytes using fluorescence resonance energy transfer (FRET)-based nanosensors. In contrast to the situation in fat cells, stimulation by extracellular L-lactate and the selective GPR81 agonists, 3-chloro-5-hydroxybenzoic acid (3Cl-5OH-BA) or 4-methyl-N-(5-(2-(4-methylpiperazin- 1-yl)-2-oxoethyl)-4-(2-thienyl)-1,3-thiazol-2-yl)cyclohexanecarboxamide (Compound 2), like adrenergic stimulation, elevated intracellular cAMP and L-lactate in astrocytes, which was reduced by the inhibition of adenylate cyclase. Surprisingly, 3Cl-5OH-BA and Compound 2 increased cytosolic cAMP also in GPR81-knock out astrocytes, indicating that the effect is GPR81-independent and mediated by a novel, yet unidentified, excitatory L-lactate receptor-like mechanism in astrocytes that enhances aerobic glycolysis and L-lactate production via a positive feedback mechanism. [ABSTRACT FROM AUTHOR]

Propionic acidemia is the accumulation of propionate in blood due to dysfunction of propionyl- CoA carboxylase. The condition causes lethargy and striatal degeneration with motor impairment in humans. How propionate exerts its toxic effect is unclear. Here, we show that intravenous administration of propionate causes dose-dependent propionate accumulation in the brain and transient lethargy in mice. Propionate, an inhibitor of histone deacetylase, entered GABAergic neurons, as could be seen from increased neuronal histone H4 acetylation in the striatum and neocortex. Propionate caused an increase in GABA (γ-amino butyric acid) levels in the brain, suggesting inhibition of GABA breakdown. In vitro propionate inhibited GABA transaminase with a Ki of ~1 mmol/l. In isolated nerve endings, propionate caused increased release of GABA to the extracellular fluid. In vivo, propionate reduced cerebral glucose metabolism in both striatum and neocortex. We conclude that propionate-induced inhibition of GABA transaminase causes accumulation of GABA in the brain, leading to increased extracellular GABA concentration, which inhibits neuronal activity and causes lethargy. Propionate-mediated inhibition of neuronal GABA transaminase, an enzyme of the inner mitochondrial membrane, indicates entry of propionate into neuronal mitochondria. However, previous work has shown that neurons are unable to metabolize propionate oxidatively, leading us to conclude that propionyl- CoA synthetase is probably absent from neuronal mitochondria. Propionate-induced inhibition of energy metabolism in GABAergic neurons may render the striatum, in which >90% of the neurons are GABAergic, particularly vulnerable to degeneration in propionic acidemia. [ABSTRACT FROM AUTHOR]

ABSTRACT Detailed knowledge about the neural circuitry connecting the hippocampus and entorhinal cortex is necessary to understand how this system contributes to spatial navigation and episodic memory. The two principal cell types of the dentate gyrus, mossy cells and granule cells, are interconnected in a positive feedback loop, by which mossy cells can influence information passing from the entorhinal cortex via granule cells to hippocampal pyramidal cells. Mossy cells, like CA3 pyramidal cells, are characterized by thorny excrescences on their proximal dendrites, postsynaptic to giant terminals of granule cell axons. In addition to disynaptic input from the entorhinal cortex and perforant path via granule cells, mossy cells may also receive monosynaptic input from the perforant path via special dendrites ascending to the molecular layer. We here report qualitative and quantitative descriptions of Golgi-stained hippocampal mossy cells in mink, based on light microscopic observations and three-dimensional reconstructions. The main focus is on the location, branching pattern, and length of dendrites, particularly those ascending to the granular and molecular layers. In mink, the latter dendrites are more numerous than in rat, but fewer than in primates. They form on average 12% (and up to 29%) of the total dendritic length, and appear to cover the terminal fields of both the lateral and medial perforant paths. In further contrast to rat, the main mossy cell dendrites in mink branch more extensively with distal dendrites encroaching upon the CA3 field. The dendritic arbors extend both along and across the septotemporal axis of the dentate gyrus, not conforming to the lamellar pattern of the hippocampus. The findings suggest that the afferent input to the mossy cells becomes more complex in species closer to primates. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Cardiac mitochondrial dysfunction has been implicated in heart failure of diverse etiologies. Generalized mitochondrial disease also leads to cardiomyopathy with various clinical manifestations. Impaired mitochondrial homeostasis may over time, such as in the aging heart, lead to cardiac dysfunction. Mitochondrial DNA (mtDNA), close to the electron transport chain and unprotected by histones, may be a primary pathogenetic site, but this is not known. Here, we test the hypothesis that cumulative damage of cardiomyocyte mtDNA leads to cardiomyopathy and heart failure. Transgenic mice with Tet-on inducible, cardiomyocyte-specific expression of a mutant uracil-DNA glycosylase 1 (mutUNG1) were generated. The mutUNG1 is known to remove thymine in addition to uracil from the mitochondrial genome, generating apyrimidinic sites, which obstruct mtDNA function. Following induction of mutUNG1 in cardiac myocytes by administering doxycycline, the mice developed hypertrophic cardiomyopathy, leading to congestive heart failure and premature death after ~2 mo. The heart showed reduced mtDNA replication, severely diminished mtDNA transcription, and suppressed mitochondrial respiration with increased Pgc-1α, mitochondrial mass, and antioxidative defense enzymes, and finally failing mitochondrial fission/fusion dynamics and deteriorating myocardial contractility as the mechanism of heart failure. The approach provides a model with induced cardiac-restricted mtDNA damage for investigation of mtDNA-based heart disease. [ABSTRACT FROM AUTHOR]

Neuroglia, the "glue" that fills the space between neurons in the central nervous system, takes active part in nerve cell signaling. Neuroglial cells, astroglia, oligodendroglia, and microglia, are together about as numerous as neurons in the brain as a whole, and in the cerebral cortex grey matter, but the proportion varies widely among brain regions. Glial volume, however, is less than one-fifth of the tissue volume in grey matter. When stimulated by neurons or other cells, neuroglial cells release gliotransmitters by exocytosis, similar to neurotransmitter release from nerve endings, or by carrier-mediated transport or channel flux through the plasma membrane. Gliotransmitters include the common neurotransmitters glutamate and GABA, the nonstandard amino acid D-serine, the high-energy phosphate ATP, and L-lactate. The latter molecule is a "buffer" between glycolytic and oxidative metabolism as well as a signaling substance recently shown to act on specific lactate receptors in the brain. Complementing neurotransmission at a synapse, neuroglial transmission often implies diffusion of the transmitter over a longer distance and concurs with the concept of volume transmission. Transmission from glia modulates synaptic neurotransmission based on energetic and other local conditions in a volume of tissue surrounding the individual synapse. Neuroglial transmission appears to contribute significantly to brain functions such as memory, as well as to prevalent neuropathologies. [ABSTRACT FROM AUTHOR]

In the brain, glutamate is an extracellular transmitter that mediates cell-to-cell communication. Prior to synaptic release it is pumped into vesicles by vesicular glutamate transporters (VGLUTs). To inactivate glutamate receptor responses after release, glutamate is taken up into glial cells or neurons by excitatory amino acid transporters (EAATs). In the pancreatic islets of Langerhans, glutamate is proposed to act as an intracellular messenger, regulating insulin secretion from b-cells, but the mechanisms involved are unknown. By immunogold cytochemistry we show that insulin containing secretory granules express VGLUT3. Despite the fact that they have a VGLUT, the levels of glutamate in these granules are low, indicating the presence of a protein that can transport glutamate out of the granules. Surprisingly, in b-cells the glutamate transporter EAAT2 is located, not in the plasma membrane as it is in brain cells, but exclusively in insulin-containing secretory granules, together with VGLUT3. In EAAT2 knock out mice, the content of glutamate in secretory granules is higher than in wild type mice. These data imply a glutamate cycle in which glutamate is carried into the granules by VGLUT3 and carried out by EAAT2. Perturbing this cycle by knocking down EAAT2 expression with a small interfering RNA, or by over-expressing EAAT2 or a VGLUT in insulin granules, significantly reduced the rate of granule exocytosis. Simulations of granule energetics suggest that VGLUT3 and EAAT2 may regulate the pH and membrane potential of the granules and thereby regulate insulin secretion. These data suggest that insulin secretion from b-cells is modulated by the flux of glutamate through the secretory granules. [ABSTRACT FROM AUTHOR]

To elucidate the possible roles of the CNS neurotransmitters glycine and GABA in neuroendocrine paracrine signalling, we investigated their localizations, and those of their transport proteins, by confocal immunofluorescence and quantitative post-embedding immuno-electron microscopy in the pancreatic islets of Langerhans. We show that A-cells contain glycine in synaptic-like microvesicles as well as in secretory granules. A-cells express the macromolecules necessary to: (1) concentrate glycine within both organelle types before release (the vesicular GABA/glycine transporter VGAT=VIAAT); and to (2) take up the transmitter from the extracellular space (the plasma membrane glycine transporter GLYT2). Also B-cells have glycine in their microvesicles and granules, but the microvesicle/cytosol ratio is lower than in A-cells, consistent with the presence of GABA (which competes with glycine for vesicular uptake) in the cytosol at a much higher concentration in B- cells than in A-cells. Both A- and B-cells contain GABA in their microvesicles and secretory granules, and the membranes of the two organelle types contain VGAT in both cell types. A-cells as well as B-cells express a plasma membrane transporter GAT3 that mediates uptake of GABA. The localization of VGAT in the cores of A-cell secretory granules, and in the secretory granule membranes in both cell types, indicates novel aspects of the mechanisms for release of glycine and GABA. The discovery that both A- and B-cells possess the molecular machinery for the evoked release of both glycine and GABA from synaptic-like microvesicles suggests that both of the principal inhibitory transmitters in the brain participate in paracrine signalling in the pancreas. [ABSTRACT FROM AUTHOR]

Recent studies implicate dendritic endocannabinoid release from subsynaptic dendrites and subsequent inhibition of neurotransmitter release from nerve terminals as a means of retrograde signaling in multiple brain regions. Here we show that type 1 cannabinoid receptor-mediated endocannabinoid signaling is not involved in the retrograde control of synaptic efficacy at inhibitory synapses between fast-spiking interneurons and pyramidal cells in layer 2/3 of the neocortex. Vesicular neurotransmitter transporters, such as vesicular glutamate transporters (VGLUTs) 1 and 2, are localized to presynaptic terminals and accumulate neurotransmitters into synaptic vesicles. A third subtype of VGLUTs (VGLUT3) was recently identified and found localized to dendrites of various cell types. We demonstrate, using multiple immunofluorescence labeling and confocal laser-scanning microscopy, that VGLUT3-like immunoreactivity is present in dendrites of layer 2/3 pyramidal neurons in the rat neocortex. Electron microscopy analysis confirmed that VGLUT3-like labeling is localized to vesicular structures, which show a tendency to accumulate in close proximity to postsynaptic specializations in dendritic shafts of pyramidal cells. Dual whole-cell recordings revealed that retrograde signaling between fast-spiking interneurons and pyramidal cells was enhanced under conditions of maximal efficacy of VGLUT3-mediated glutamate uptake, whereas it was reduced when glutamate uptake was inhibited by incrementing concentrations of the nonselective VGLUT inhibitor Evans blue (0.5-5.0 µM) or intracellular Cl- concentrations (4 -145 mM). Our results present further evidence that dendritic vesicular glutamate release, controlled by novel VGLUT isoforms, provides fast negative feedback at inhibitory neocortical synapses, and demonstrate that glutamate can act as a retrograde messenger in the CNS. [ABSTRACT FROM AUTHOR]