(Press-News.org) Bioengineers from the University of California, San Diego developed an explanation for why some types of neurons die sooner than others in the brains of people with Alzheimer's disease. These insights, published in the journal Nature Biotechnology on November 21, come from detailed models of brain energy metabolism developed in the Department of Bioengineering at the UC San Diego Jacobs School of Engineering.
The Alzheimer's insights demonstrate how fundamental insights on human metabolism can be gleaned from computer models that incorporate large genomic and proteomic data sets with information from biochemical studies. UC San Diego bioengineering professor Bernhard Palsson and his students and collaborators first developed this "in silico" modeling approach for E. coli and other prokaryotes, and later extended it to human tissues.
The Nature Biotechnology paper describes the first time this modeling approach has been used to capture how the metabolism of specific human cell types affect the metabolism of other cell types.
"In human tissues, different cells have different roles. We're trying to predict how the behavior of one cell type will affect the behavior of other cell types," said Nathan Lewis, a Ph.D. candidate in the Department of Bioengineering at the UC San Diego Jacobs School of Engineering and the first author on the Nature Biotechnology paper, which also includes authors from the University of Heidelberg, Massachusetts Institute of Technology, and the German Cancer Research Center (DKFZ).
Similar approaches can be used to identify potential off-target effects of drugs, provide insights on disease progression, and offer new tools for uncovering the underlying biological mechanisms in a wide range of human tissues and cell types.
Why Some Neurons Die First in the Alzheimer's Brain
In the brains of people with Alzheimer's disease, certain cells, such as glutamatergic 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 microenvironment and metabolic interactions between specific cell types.
The models for each cell can be represented like a circuit, with certain inputs and outputs. For example, sugars, like glucose, are inputs, and the models detail how these inputs are used to build cell parts and secrete byproducts as outputs. The metabolic models the bioengineers built provide a means to study these networks.
For example, each cell type has different biochemical pathways that can take the sugars from point A to B. If you knock out a gene in between, the network might find a different route, produce different products, or predict cell death. When models for multiple cells are combined, additional insight can be gained since the inputs and outputs of each model begin to affect the other cells.
"There are many potential applications for these models. For example, this modeling approach could be useful for predicting off target side effects of drugs. You could theoretically take a cell line, throw a drug at it and see which metabolic pathways are significantly affected. Thus, you could decrease the amount of resources spent on drug development if the model suggests negative side effects that may cause it to fail," said Lewis.
INFORMATION:
"Large-scale in silico modeling of metabolic interactions between cell types in the human brain," by Nathan E Lewis (1), Gunnar Schramm (2,5), Aarash Bordbar (1), Jan Schellenberger (3), Michael P Andersen (1), Jeffrey K Cheng (1), Nilam Patel (1), Alex Yee (1), Randall A Lewis (4), Roland Eils (2,5), Rainer König (2,5) & Bernhard Ø Palsson (1); published online on November 21, 2010 in Nature Biotechnology.
(1) Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
(2) Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg, Germany.
(3) Bioinformatics Program, University of California, San Diego, La Jolla, California, USA.
(4) Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
(5) Department of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
This work was funded in part by a Fulbright fellowship, a National Science Foundation IGERT Plant Systems Biology training grant (no. DGE-0504645), a US National Institutes of Health grant 2R01GM068837_05A1 and the Helmholtz Alliance on Systems Biology and the BMBF by the NGFN+ neuroblastoma project ENGINE.
Metabolism models may explain why Alzheimer's disease kills some neuron types first
Alzheimer’s insights derived from models of brain energy metabolism created in the UC San Diego Department of Bioengineering
2010-12-07
ELSE PRESS RELEASES FROM THIS DATE:
Fewer guessing games for lung cancer patients
2010-12-07
Reston, Va. — A study published in the December issue of The Journal of Nuclear Medicine identified positron emission tomography/computed tomography (PET/CT) scans as a potentially useful tool for predicting local recurrence in lung cancer patients treated with radiofrequency ablation (RFA). RFA, which uses localized thermal energy to kill cancer cells, is increasingly used as an alternative treatment for patients unable to undergo surgery or other therapies to treat lung cancer.
"This study reinforces the utility of 18F-FDG-PET imaging in cancer detection and follow-up ...
Imitating someone's accent makes it easier to understand them
2010-12-07
In conversation, we often imitate each other's speech style and may even change our accent to fit that of the person we're talking to. A recent study in Psychological Science, a journal of the Association for Psychological Science, suggests that imitating someone who speaks with a regional or foreign accent may actually help you understand them better.
"If people are talking to each other, they tend to sort of move their speech toward each other," says Patti Adank, of the University of Manchester, who cowrote the study with Peter Hagoort and Harold Bekkering from Radboud ...
Missouri grapes hold key to improving world grape production
2010-12-07
In a few years, a sip of Cabernet Sauvignon, Merlot or Pinot Noir may include a taste of the "Show-Me" State. The state grape of Missouri – the Norton variety grown at many vineyards around the state – is resistant to powdery mildew, a fungal pathogen that affects winemaking grapes around the world. Now, researchers at the University of Missouri are working to identify valuable genes from the Norton grape for eventual transfer into other grapes to make them less susceptible to mildew, decrease fungicide use and increase world-wide grape production.
Walter Gassmann, ...
Early physical therapy for low back pain associated with less subsequent health care utilization
2010-12-07
The American Physical Therapy Association (APTA) is pointing to a new study on low back pain in Medicare patients in its efforts to encourage the newly established Center for Medicare and Medicaid Innovation to promptly launch a demonstration project on direct access to physical therapist services that was recommended in the recent health reform law. The study, published in the journal Spine, showed Medicare patients who received physical therapy in the acute phase following an episode of low back pain were less likely to receive epidural steroid injections, lumbar surgery, ...
Illinois study: Ginseng just got better -- not as bitter
2010-12-07
URBANA – University of Illinois scientists have learned to mask the bitterness of ginseng, a common ingredient of energy drinks.
"Consumers like to see ginseng on a product's ingredient list because studies show that it improves memory, enhances libido and sexual performance, boosts immunity, and alleviates diabetes. But the very compounds that make ginseng good for you also make it taste bitter," said Soo-Yeun Lee, a U of I associate professor of food science and human nutrition.
In an earlier study, Lee and U of I professor of food chemistry Shelly J. Schmidt found ...
Optics Express focus issue on chalcogenide photonics: Fabrication, devices and applications
2010-12-07
WASHINGTON, Dec. 6—Recent progress in chalcogenide glass photonics has been driven by scientific and technological challenges in a variety of areas. These range from increased demand for bandwidth in optical communications, to the emergence of bio-health hazards associated with hazardous microorganisms that absorb at mid-infrared wavelengths, to defense applications that require bright mid-infrared sources. Additionally, chalcogenide glass provides a platform for fundamental investigations of light-matter interactions in nanophotonic structures, such as photonic crystals ...
Fleshing out the life histories of dead whales
2010-12-07
Dead whales that sink down to the seafloor provide a feast for deep-sea animals that can last for years. Previous research suggested that such "whale falls" were homes for unique animals that lived nowhere else. However, after sinking five whale carcasses in Monterey Canyon, researchers from the Monterey Bay Aquarium Research Institute (MBARI) found that most of the animals at these sites were not unique to whale falls, but were common in other deep-sea environments as well. Nonetheless, the whale-fall communities did include a few very abundant animals that were "bone ...
A flu vaccine that lasts
2010-12-07
WHAT: The costly, time-consuming process of making, distributing and administering millions of seasonal flu vaccines would become obsolete if researchers could design a vaccine that confers decades-long protection from any flu virus strain. Making such a universal influenza vaccine is feasible but licensing it may require innovation on several fronts, including finding new ways to evaluate the efficacy of vaccine candidates in clinical trials, conclude scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. ...
Rice physicists help unravel mystery of repetitive DNA segments
2010-12-07
HOUSTON -- (Dec. 6, 2010) -- With new tools that can grab individual strands of DNA and stretch them like rubber bands, Rice University scientists are working to unravel a mystery of modern genomics. Their latest findings, which appear in Physical Review Letters, offer new clues about the physical makeup of odd segments of DNA that have just one DNA base, adenine, repeated dozens of times in a row.
These mysterious "poly(dA) repeats" are sprinkled throughout the human genome. Scientists have also found them in the genomes of animals, plants and other species over the ...
Why married men tend to behave better
2010-12-07
EAST LANSING, Mich. — Researchers have long argued that marriage generally reduces illegal and aggressive behaviors in men. It remained unclear, however, if that association was a function of matrimony itself or whether less "antisocial" men were simply more likely to get married.
The answer, according to a new study led by a Michigan State University behavior geneticist, appears to be both.
In the December issue of the Archives of General Psychiatry, online today, S. Alexandra Burt and colleagues found that less antisocial men were more likely to get married. Once ...
LAST 30 PRESS RELEASES:
Scientists unlock secrets behind flowering of the king of fruits
Texas A&M researchers illuminate the mysteries of icy ocean worlds
Prosthetic material could help reduce infections from intravenous catheters
Can the heart heal itself? New study says it can
Microscopic discovery in cancer cells could have a big impact
Rice researchers take ‘significant leap forward’ with quantum simulation of molecular electron transfer
Breakthrough new material brings affordable, sustainable future within grasp
How everyday activities inside your home can generate energy
Inequality weakens local governance and public satisfaction, study finds
Uncovering key molecular factors behind malaria’s deadliest strain
UC Davis researchers help decode the cause of aggressive breast cancer in women of color
Researchers discovered replication hubs for human norovirus
SNU researchers develop the world’s most sensitive flexible strain sensor
Tiny, wireless antennas use light to monitor cellular communication
Neutrality has played a pivotal, but under-examined, role in international relations, new research shows
Study reveals right whales live 130 years — or more
Researchers reveal how human eyelashes promote water drainage
Pollinators most vulnerable to rising global temperatures are flies, study shows
DFG to fund eight new research units
Modern AI systems have achieved Turing's vision, but not exactly how he hoped
Quantum walk computing unlocks new potential in quantum science and technology
Construction materials and household items are a part of a long-term carbon sink called the “technosphere”
First demonstration of quantum teleportation over busy Internet cables
Disparities and gaps in breast cancer screening for women ages 40 to 49
US tobacco 21 policies and potential mortality reductions by state
AI-driven approach reveals hidden hazards of chemical mixtures in rivers
Older age linked to increased complications after breast reconstruction
ESA and NASA satellites deliver first joint picture of Greenland Ice Sheet melting
Early detection model for pancreatic necrosis improves patient outcomes
Poor vascular health accelerates brain ageing
[Press-News.org] Metabolism models may explain why Alzheimer's disease kills some neuron types firstAlzheimer’s insights derived from models of brain energy metabolism created in the UC San Diego Department of Bioengineering