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Metabolism models may explain why Alzheimer's disease kills some neuron types first
Date:12/6/2010

c and cholinergic neurons, tend to die in much larger numbers in moderate stages of Alzheimer's disease, while GABAergic neurons are relatively unaffected until later stages of the disease.

"There is a big question as to what is causing this cell-type specificity," said Lewis.

The researchers built computational models that captured the metabolic interactions between each of the three neuron types and their associated astrocyte cells. Next, the bioengineers knocked down α-ketoglutarate, a gene known to be damaged in patients with Alzheimer's disease, and let their models of brain metabolism run to see what happens.

The results from the models agreed with clinical data. When the bioengineers disrupted the α-ketoglutarate enzyme in the models for cholinergic and glutamatergic neurons, the metabolic rate of these neurons dropped, leading to cell death. "But then you have the GABAergic neurons that show no effect. So the cell types that are known to be lost early on in Alzheimer's show slowed metabolic rates," explained Lewis.

Analysis of their models then led the bioengineers to the biochemical pathways that allowed the GABAergic neurons to be relatively unaffected despite the disrupted gene.

"We looked at what upstream is allowing this and found a GABA-specific enzyme called glutamate decarboxylase," said Lewis.

When the researchers added this enzyme to the models of the other neuron types, the metabolic rates of these neurons improved as well. Thus the model allowed the researchers to identify a gene and how it contributes to the whole cell to potentially prolong the life of certain cells in Alzheimer's disease.

Large Scale Modeling of Metabolic Interactions

The new Nature Biotechnology paper uses the Alzheimer's brain study as an example of how to build models of metabolism that go one level deeper than previous work by taking into account the tissue microenvironm
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Contact: Daniel Kane
dbkane@ucsd.edu
858-534-3262
University of California - San Diego
Source:Eurekalert  

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