Projects / Programmes
Dysregulation of astroglial metabolism in neurodegeneration
| Code |
Science |
Field |
Subfield |
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
neurodegeneration, astroglia, brain, noradrenergic system, metabolism, glucose, lipids
Researchers (10)
Organisations (2)
Abstract
Although the brain represents only 2% of the total body mass, it utilizes ~20% of the total plasma glucose. Neurons are the most energy consuming cells in the brain (consume 70–80% of the total energy), with the remaining energy being utilized by other cell types, including glial cells (astrocytes, oligodendrocytes, microglia). During elevated cognitive activity neuronal metabolism relies mostly on glial cells, in particular astrocytes, abundant and heterogeneous subset of glial cells with many homeostatic functions. With their numerous processes astrocytes ensheath neurons and blood vessels and act as an intermediate for delivering plasma fuel substrates to neurons. Neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis) are age-related incurable chronic diseases of the nervous system. Many of them are proteinopathies characterized by the accumulation of specific proteins (e.g. amyloid-b, tau, ?-synuclein, TDP-43) within brain cells or in the brain parenchyma, resulting in progressive structural and functional degeneration and/or death of neurons. Changes in the brain metabolism (hypometabolism) have been observed in the early stages of neurodegenerative diseases and may be a primary initiation trigger for the diseases, what may represent an ef?cient therapeutic target to treat the age-related neurodegenerative diseases. Recent studies suggest that astrocytes contribute to neuronal cell death and the pathology of neurodegenerative diseases and may even play the leading part in the disease onset and development. However, the molecular mechanisms underlying the astroglial-mediated neuronal toxicity are largely unknown. Astrocytes abundantly express adrenergic receptors and are the main target of the locus coeruleus-noradrenergic system in the brain that is one of the most important regulators of brain metabolism on-demand. Noradrenaline, when released from the noradrenergic neurons, binds to adrenergic receptors on astrocytes and changes intracellular concentration of cAMP and calcium. This activates astroglial metabolism, enhancing glucose uptake, glycogenolysis, aerobic glycolysis with lactate production, and subsequently providing metabolic support for neurons in the form of lactate. It has been shown that noradrenergic system begins to deteriorate in the early stages of neurodegeneration. Since neuronal metabolism relies on astrocytes and noradrenergic system, we hypothesize that the astroglial adrenergic signaling that controls astroglial metabolism and subsequently provides metabolic fuels for neurons is dysregulated, which contributes to pathology during neurodegeneration. In this Project we will use genetic modifications to introduce pathological protein aggregates typical for neurodegeneration into rat isolated astrocytes or into the brain of the well-established invertebrate neurodegeneration animal model Drosophila melanogaster and study the effect of aggregated proteins on astroglial metabolism. We will measure changes in the intracellular levels of calcium, cAMP and metabolites in real-time with confocal and 2-photon microscopy, using recently developed genetically encoded fluorescent FRET-based nanosensors for cAMP, glucose, lactate that will be selectively expressed in living astrocytes, and intracellular fluorescent calcium indicators. We will expose astrocytes to noradrenergic (in vitro studies on rat isolated astrocytes) or octopaminergic stimulation, resembling noradrenergic stimulation in mammals (studies in vivo on astrocytes in Drosophila brain). We will also establish whether protein aggregates affect lipid metabolism in astrocytes with fluorescent lipid dyes to label lipid droplets. With the identification of molecular mechanisms underlying astroglial metabolic alterations in neurodegenerative diseases, we will generate new insights into the molecular mechanisms of age-related degeneration, a topic with strong translational potential of developing therapeutic
