Neuromet - Neurometabolism in health and diseases

We study the biochemical and cellular mechanisms underlying energy and amino acid metabolism in the mammalian brain, as well as metabolic brain disorders.

Neuromatabolism

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Research projects

 

 

 

Decline in cerebral glucose metabolism is well established as one of the early pathogenic markers of Alzheimer’s disease (AD) and a potential initiator of neurodegeneration. Impaired insulin signaling, changes in expression and regulation of key enzymes of glucose metabolism and mitochondrial dysfunction all contribute to this hypometabolism.

In NeuroMet we want to characterize the brain hypometabolism in early AD. How does the reduced glucose metabolism develop and how does it affect the disease progression and the vulnerability of neurons and astrocytes?

We are using novel in-vitro models based on neurons and astrocytes either from patient derived tissue or an AD mouse model. By incubating cell cultures with 13C-labeled substrates and subsequently analyzing tissue extracts using nuclear magnetic resonance spectroscopy (NMRS) and mass spectrometry (MS), we get a detailed mapping of the metabolism in the AD models. Furthermore, by using Seahorse Extracellular Flux Analyzer we are able to monitor oxygen consumption to assess the oxidative capacity in the AD models. To evaluate the vulnerability of the cells we apply different AD stressors.

This project will contribute to validation of the AD models used and pave the way for a novel understanding of the coupling between brain energy metabolism and AD. This may lead to a highly needed new approach in AD treatment.

Projects members

Helle S. Waagepetersen
Professor (Head of unit)
helle.waagepetersen@sund.ku.dk
Phone: +45 35 33 64 70

Jakob D. Nissen
Blanca Irene Aldana Garcia
Sofie K. Christensen
Jens V. Andersen

Collaborators

  • Heikki Tanila, Uni. Eastern Finland
  • Poul Hyttel & Kristine Freude, UCPH

 

 

 

 

 

 

 

Type 2 diabetes mellitus (T2DM) has reached pandemic proportions as it is estimated that around 7% of the adult world population suffer from T2DM. The effect of T2DM on the human CNS has gained more attention recently as it is becoming evident that T2DM is a risk factor for the development of Alzheimer’s disease. Altered brain energy metabolism is a preclinical symptom of dementia and it has been hypothesized that this could be a mechanistic link between T2DM and Alzheimer’s diseases.

We are studying the effect of T2DM on brain energy metabolism using a common T2DM animal model: the db/db mouse. This transgenic mouse expresses dysfunctional leptin receptors, leading to hyperglycemia and obesity due to overeating.

By investigating brain energy metabolism in acutely isolated brain slices, mitochondria and synaptosomes, we hope to mechanistically unravel some of the mechanisms at work. We apply several different experimental setups and analytical methods, including incubations with stable isotopes (13C) with subsequent analysis by GCMS and HPLC and state-of-the-art mitochondrial assays using the SeaHorse XFe96 flux analyzer.

Our research could help to prevent dementia amplified by T2DM or even reveal possible basal mechanisms to the development of Alzheimer’s disease.

Project members

Helle S. Waagepetersen 
Professor (Head of unit)
helle.waagepetersen@sund.ku.dk
Phone: +45 35 33 64 70

Jakob D. Nissen
Sofie K. Christensen
Jens V. Andersen
Lene Arildsen

Collaborators

Majid Sheykhzade, UCPH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

How does the brain control energy homeostasis- at the same time always being prepared for signaling while not wasting energy?

In the brain energetics project we investigate mechanisms regulating neuronal and astrocytic energy expenditure and production.

We use neurons and astrocytes in culture and isolated mitochondria to monitor respiration, ATP production, calcium signaling and membrane potential changes under different stimuli.

We aim to gain a better understanding of brain energetics to enhance knowledge about mechanisms involved in pathological states such as ischemia after stroke and neurodegenerative diseases.

Projects members

Helle S. Waagepetersen 
Professor (Head of unit)
helle.waagepetersen@sund.ku.dk
Phone: +45 35 33 64 70

Anne B. Walls
Caroline M. Voss
Sofie K. Christensen

Collaborators

  • Lasse K. Bak
  • Brian MacVicar, Uni. of British Columbia, Vancouver

 

 

 

 

 

 

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system. Glutamate is unique as neurotransmitter due to its abundance and its central role in intermediary carbon and nitrogen metabolism. Glutamate metabolism in the brain is compartmentalized and neurons are completely dependent on the ability of astrocytes to synthesize glutamine, the glutamate precursor.

We are eager to complete the puzzle of the role of glutamate and glutamine in brain energetics. To what extent is neuronal activity dependent on the use of amino acids, such as glutamate and glutamine, as energy substrates?

In order to unravel this we use transgenic mouse models in which key proteins are knocked out. We map metabolism employing 13C and 15N labeled substrates, in mice, acute brain slices, in cultured astrocytes and neurons and in synaptosomes. Brain energetics is investigated in isolated mitochondria using the Seahorse technology and on-line ATP assays.

Brain metabolism is challenged in hepatic encephalopathy due to an increased brain ammonia level. Astrocytes are believed to be the major assimilators of ammonia in brain via glutamine synthesis. But how do neurons cope even small amounts of ammonia, we are investigating neuronal nitrogen metabolism in a mouse deficient of their only enzyme assimilating ammonia, namely glutamate dehydrogenase.

Projects members

Helle S. Waagepetersen 
Professor (Head of unit)
helle.waagepetersen@sund.ku.dk
Phone: +45 35 33 64 70

Anne B. Walls
Blanca I. Aldana
Caroline M. Voss
Mehdi Khorramis 

Collaborators

  • Susanne Keiding, Michael Sørensen, Peter Ott, Hendrik Vilstrup, AU
  • Pierre Maechler, Uni. of Geneva
  • Svante Pääbo, Max Planck Inst. Leipzig
  • Ioannis Zaganas, Uni. of Crete
  • Paul Rosenberg, Harvard Uni.

 

 

 

 

 

 

 

 

 

Group leader

Group Leader

Blanca Aldana
Associate Professor

Phone: +45 31541804
blanca.aldana@sund.ku.dk

Group members

Name Title Phone E-mail
Nielsen, Heidi Marie Laboratory Technician +4535336333 E-mail