ASTROAGE

Astrocytes in aging brain exhibit altered glutamate homeostasis: Implications for age related cognitive decline?

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 Obiettivo del progetto (Objective)

'Aging affects the brain in many ways, most notably by impairing memory function. On a cellular level, aging causes changes in synaptic plasticity and downregulation of energy metabolism. As our understanding of the importance of astrocytes in brain is increasing, it is clear that the knowledge on how aging affects astrocytes is lacking. The aim is, therefore, to elucidate the role of astrocytes in aging and how homeostasis of the neurotransmitter glutamate and energy metabolism alters with age and how this correlates to cognitive decline. The approach is to investigate astrocyte uptake of glutamate and energy metabolism in hippocampal slices from neonatal, adult and aged mice. Initially the effects of aging on astrocyte glutamate uptake will be quantified by measuring synaptically evoked glutamate transporter currents. Alterations in metabolic pathways will be evaluated by 13C metabolic mapping employing mass spectrometry and NMR spectroscopy. Besides being an excitatory neurotransmitter, glutamate is a substrate for energy production via conversion to a-ketoglutarate by glutamate dehydrogenase (GDH). Increased input of glutamate into the TCA-cycle may counteract a reduced energy metabolism during aging. Therefore, I will investigate the effect of GDH activity during aging, using a GDH knock out mouse and a transgenic model expressing GDH2 in addition to GDH1. To correlate the effects on uptake and metabolism to cognitive decline, I will investigate the effect of GDH activity on synaptic plasticity and spatial memory. By measuring long term potentiation in hippocampal slices and evaluating spatial memory capacity of the animals, I will be able to draw conclusions concerning the effect of altered glutamate homeostasis on cognitive decline. The project takes a grip on the issue of astrocytes in cognitive decline and aging from both the in vivo and in vitro angle. Therefore, it will contribute with new, valuable information on the role of astrocytes in the aging brain.'

Introduzione (Teaser)

Ageing affects the brain, especially the memory. European researchers have investigated how energy usage in the brain may change as old age approaches.

Descrizione progetto (Article)

The effects of ageing on brain function can seriously affect otherwise healthy individuals. In the ageing brain, most research has focused on the neurons while the importance of astrocytes, the most numerous cell type in brain, have been largely ignored. The knowledge on the multitude of functions performed by astrocytes is constantly increasing, but details of how ageing can affect astrocyte energy metabolism remain incomplete.

Funded by the EU, the ASTROAGE (Astrocytes in aging brain exhibit altered glutamate homeostasis: Implications for age related cognitive decline?) project looked at the consequences of ageing on astrocytes. The researchers compared the metabolic activity in astrocytes in the hippocampus of young mice at 4 and 22 months old. Using 13-C labelled energy substrates such as glutamate, glucose and acetate they investigated age-related effects on neuronal and astrocytic metabolism, with special emphasis on glutamate since it is primarily taken up by astrocytes and can be a valuable source of energy under low-glucose conditions.

Project results showed that the metabolic properties of the older mouse astrocytes are geared towards more efficient use of glutamate for energy production. Glycogen storage also increases in the old brain which may be an indication of altered glucose metabolism. Moreover, intermediates in the tricarboxylic acid (TCA) cycle, fumarate and citrate, are also differentially regulated in the ageing brain, which could indicate an imbalance in reactions in the cycle.

Researchers also investigated changes in levels of glutamate dehydrogenase (GDH), an enzyme that converts glutamate to alpha-ketoglutarate, an intermediate in the TCA cycle. Indeed, results showed that hippocampal slices exhibit a very high level of GDH activity, but no age-related differences could be proven. Overall findings indicate a very close connection between glutamate input to the TCA cycle through GDH activity and glucose metabolism.

As any disturbance in energy production homeostasis may lead to neurodegeneration, a thorough understanding of the contribution of astrocytes to brain ageing processes is crucial to counteract cognitive decline in older people. ASTROAGE has laid a firm knowledge foundation for more in-depth studies particularly relevant in an ageing Europe.