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Mitochondrial and Brain Stuff....New Discoveries and ?????

Discussion in 'The Epi-Paleo Diet' started by chocolate, Mar 27, 2012.

  1. chocolate

    chocolate Silver

    http://www.psypost.org/2012/04/compound-reduces-autism-like-behaviors-in-mice-11349





    Compound reduces autism-like behaviors in mice



    Crawley’s team followed-up on clues from earlier findings hinting that inhibitors of the receptor, called mGluR5, might reduce ASD symptoms. This class of agents – compounds similar to GRN-529, used in the mouse study – are in clinical trials for patients with the most common form of inherited intellectual and developmental disabilities, Fragile X syndrome, about one third of whom also meet criteria for ASDs.



    Moreover, GRN-529 almost completely stopped repetitive jumping in another strain of mice.




    “These inbred strains of mice are similar, behaviorally, to individuals with autism for whom the responsible genetic factors are unknown, which accounts for about three fourths of people with the disorders,” noted Crawley. “Given the high costs – monetary and emotional – to families, schools, and health care systems, we are hopeful that this line of studies may help meet the need for medications that treat core symptoms.”
     
  2. chocolate

    chocolate Silver

    Differences in dopamine may determine how hard people work

    http://www.psypost.org/2012/05/differences-in-dopamine-may-determine-how-hard-people-work-11424



    Dopamine pathwaysWhether someone is a “go-getter” or a “slacker” may depend on individual differences in the brain chemical dopamine, according to new research in the May 2 issue of The Journal of Neuroscience. The findings suggest that dopamine affects cost-benefit analyses.



    The study found that people who chose to put in more effort — even in the face of long odds — showed greater dopamine response in the striatum and ventromedial prefrontal cortex, areas of the brain important in reward and motivation. In contrast, those who were least likely to expend effort showed increased dopamine response in the insula, a brain region involved in perception, social behavior, and self-awareness.



    Researchers led by Michael Treadway, a graduate student working with David Zald, PhD, at Vanderbilt University, asked participants to rapidly press a button in order to earn varying amounts of money. Participants got to decide how hard they were willing to work depending on the odds of a payout and the amount of money they could win. Some accepted harder challenges for more money even against long odds, whereas less motivated subjects would forgo an attempt if it cost them too much effort.



    In a separate session, the participants underwent a type of brain imaging called positron emission tomography (PET) that measured dopamine system activity in different parts of the brain. The researchers then examined whether there was a relationship between each individual’s dopamine responsiveness and their scores on the motivational test described earlier.



    You should read the warm adapted rat section that follows. lol
     
  3. chocolate

    chocolate Silver

    http://www.psypost.org/2012/05/freezing-parkinsons-in-its-tracks-11404



    Parkinson’s disease, a disorder which affects movement and cognition, affects over a million Americans, including actor Michael J. Fox, who first brought it to the attention of many TV-watching Americans. It’s characterized by a gradual loss of neurons that produce dopamine. Mutations in the gene known as DJ-1 lead to accelerated loss of dopaminergic neurons and result in the onset of Parkinson’s symptoms at a young age.



    The ability to modify the activity of DJ-1 could change the progress of the disease, says Dr. Nirit Lev, a researcher at Tel Aviv University’s Sackler Faculty of Medicine and a movement disorders specialist at Rabin Medical Center. Working in collaboration with Profs. Dani Offen and Eldad Melamed, Dr. Lev has now developed a peptide which mimics DJ-1′s normal function, thereby protecting dopamine- producing neurons. What’s more, the peptide can be easily delivered by daily injections or absorbed into the skin through an adhesive patch.



    Based on a short protein derived from DJ-1 itself, the peptide has been shown to freeze neurodegeneration in its tracks, reducing problems with mobility and leading to greater protection of neurons and higher dopamine levels in the brain. Dr. Lev says that this method, which has been published in a number of journals including the Journal of Neural Transmission, could be developed as a preventative therapy.
     
  4. chocolate

    chocolate Silver

    http://www.nature.com/news/remote-controlled-genes-trigger-insulin-production-1.10585

    Remote-controlled genes trigger insulin production



    Nanoparticles heated by radio waves switch on genes in mice

    Researchers have remotely activated genes inside living animals, a proof of concept that could one day lead to medical procedures in which patients’ genes are triggered on demand.



    The work, in which a team used radio waves to switch on engineered insulin-producing genes in mice, is published today in Science1.



    Jeffrey Friedman, a molecular geneticist at the Rockefeller University in New York and lead author of the study, says that in the short term, the results will lead to better tools to allow scientists to manipulate cells non-invasively. But with refinement, he thinks, clinical applications could also be possible.



    Friedman and his colleagues coated iron oxide nanoparticles with antibodies that bind to a modified version of the temperature-sensitive ion channel TRPV1, which sits on the surface of cells. They injected these particles into tumours grown under the skins of mice, then used the magnetic field generated by a device similar to a miniature magnetic-resonance-imaging machine to heat the nanoparticles with low-frequency radio waves. In turn, the nanoparticles heated the ion channel to its activation temperature of 42 °C. Opening the channel allowed calcium to flow into cells, triggering secondary signals that switched on an engineered calcium-sensitive gene that produces insulin.



    After 30 minutes of radio-wave exposure, the mice's insulin levels had increased and their blood sugar levels had dropped.

     
  5. chocolate

    chocolate Silver

    http://www.newsdaily.com/stories/bre84509x-us-brain-neurodegeneration/

    Scientists "switch off" brain cell death in mice

    LONDON, May 6, 2012 (Reuters) — Scientists have figured out how to stop brain cell death in mice with brain disease and say their discovery deepens understanding of the mechanisms of human neurodegenerative diseases such as Alzheimer's and Parkinson's.

    British researchers writing in the journal Nature said they had found a major pathway leading to brain cell death in mice with prion disease, the mouse equivalent of Creutzfeld-Jacob Disease (CJD).



    They then worked out how to block it, and were able to prevent brain cells from dying, helping the mice live longer.



    The finding, described by one expert as "a major breakthrough in understanding what kills neurons", points to a common mechanism by which brain diseases such as Alzheimer's, Parkinson's and CJD damage the nerve cells.



    In neurodegenerative diseases, proteins "mis-fold" in a various ways, leading to a buildup of misshapen proteins, the researchers explained in the study.



    These misshapen proteins form the plaques found in the brains of patients with Alzheimer's and the Lewy bodies found in Parkinson's disease.



    "What's exciting is the emergence of a common mechanism of brain cell death, across a range of different neurodegenerative disorders, activated by the different mis-folded proteins in each disease," said Giovanna Mallucci, who led the research at the University of Leicester's toxicology unit.



    "The fact that in mice with prion disease we were able to manipulate this mechanism and protect the brain cells means we may have a way forward in how we treat other disorders," she said in a statement about the work.



    An estimated 18 million people worldwide suffer from Alzheimer's, and Parkinson's is thought to affect around one in 100 people over the age of 60. In these diseases, neurons in the brain die, destroying the brain from the inside.



    But why the neurons die has remained an unsolved mystery, presenting an obstacle to developing effective treatments and to being able to diagnose the illnesses at early stages when medicines might work better.



    TRIGGER



    Mallucci's team found that the buildup of mis-folded proteins in the brains of mice with prion disease activated a natural defense mechanism in cells, which switches off the production of new proteins.



    This would normally switch back on again, the researchers explained, but in these ill mice the continued build-up of misshapen proteins keeps the switch turned off. This is the trigger point leading to brain cell death, because key proteins essential for cell survival are not made.



    They found the brain cells were protected, protein levels were restored and synaptic transmission - the way brain cells signal to each other - was re-established. The mice also lived longer, even though only a very small part of their brains had been treated.




    Eric Karran, director of research at the charity Alzheimer's Research UK, said while the research was still at an early stage, the results were exciting.



    "While neurodegenerative diseases can have many different triggers, this study suggests that they may act through a common mechanism to damage nerve cells. The findings present the appealing concept that one treatment could have benefits for a range of different diseases," he said.



    Roger Morris, a professor of molecular neurobiology at King's College London who was not involved in the work, said the finding was "a major breakthrough in understanding what kills neurons in neurodegenerative disease".



    "There are good reasons for believing this response, identified with prion disease, applies also to Alzheimer's and other neurodegenerative diseases," he said.
     
  6. chocolate

    chocolate Silver

    http://www.ncbi.nlm.nih.gov/pubmed/16098089

    Melatonin reduces oxidative stress and increases gene expression in the cerebral cortex and cerebellum of aluminum-exposed rats.

    Esparza JL, Gómez M, Rosa Nogués M, Paternain JL, Mallol J, Domingo JL.

    Source



    Laboratory of Toxicology and Environmental Health, School of Medicine, Rovira i Virgili University, Reus, Spain.

    Abstract



    The pro-oxidant activity of aluminum (Al), the protective role of exogenous melatonin, as well as the mRNA levels of some antioxidant enzymes, were determined in cortex and cerebellum of rats following exposure to Al and/or melatonin. Two groups of male rats received intraperitoneal injections of Al lactate or melatonin at doses of 7 mg Al/kg/day and 10 mg/kg/day, respectively, for 11 wk. A third group of animals received concurrently Al lactate (7 mg Al/kg/day) plus melatonin (10 mg/kg/day) during the same period. A fourth group of rats was used as control. At the end of the treatment, the cerebral cortex and cerebellum were removed and processed to examine the following oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase, glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Moreover, gene expression of Cu-ZnSOD, MnSOD, GPx and CAT was evaluated by real-time RT-PCR. On the other hand, Al, Fe, Mn, Cu and Zn concentrations were determined in cortex and cerebellum of rats. Oxidative stress was promoted in both neural regions following Al administration, resulting from the pro-oxidant activity related with an increase in tissue Al concentrations. In contrast, melatonin exerted an antioxidant action which was related with an increase in the mRNA levels of the antioxidant enzymes evaluated. The results of the present investigation emphasize the potential use of melatonin as a supplement in the therapy of neurological disorders in which oxidative stress is involved.
     
  7. chocolate

    chocolate Silver

    http://www.sciencedaily.com/releases/2008/08/080818101335.htm

    Potential Alzheimer's, Parkinson's Cure Found In Century-Old Drug

    ScienceDaily (Aug. 18, 2008) — A new study conducted by researchers at Children's Hospital & Research Center Oakland shows that a century-old drug, methylene blue, may be able to slow or even cure Alzheimer's and Parkinson's disease. Used at a very low concentration – about the equivalent of a few raindrops in four Olympic-sized swimming pools of water – the drug slows cellular aging and enhances mitochondrial function, potentially allowing those with the diseases to live longer, healthier lives.

    A paper on the methylene blue study, conducted by Hani Atamna, PhD, and a his team at Children's, was published in the March 2008 issue of the Federation of American Societies for Experimental Biology (FASEB) Journal. Dr. Atamna's research found that methylene blue can prevent or slow the decline of mitochondrial function, specifically an important enzyme called complex IV. Because mitochondria are the principal suppliers of energy to all animal and human cells, their healthy function is critical.
     
  8. donkjellberg

    donkjellberg Silver

    Chocolate, you are an awesome researcher. I probably speak for many in expressing gratitude for your thoughtful inquiries.
     
  9. chocolate

    chocolate Silver

    http://www.ijponline.net/content/37/1/60

    Background



    Attention deficit hyperactivity disorder is a behavioral syndrome of childhood characterized by inattention, hyperactivity and impulsivity. There were many etiological theories showed dysfunction of some brain areas that are implicated in inhibition of responses and functions of the brain. Minerals like zinc, ferritin, magnesium and copper may play a role in the pathogenesis and therefore the treatment of this disorder.



    Results



    Zinc, ferritin and magnesium levels were significantly lower in children with attention deficit hyperactivity disorder than controls (p value 0.04, 0.03 and 0.02 respectively), while copper levels were not significantly different (p value 0.9). Children with inattentive type had significant lower levels of zinc and ferritin than controls (p value 0.001 and 0.01 respectively) with no significant difference between them as regards magnesium and copper levels (p value 0.4 and 0.6 respectively). Children with hyperactive type had significant lower levels of zinc, ferritin and magnesium than controls (p value 0.01, 0.02 and 0.02 respectively) with no significant difference between them as regards copper levels (p value 0.9). Children with combined type had significant lower levels of zinc and magnesium than controls (p value 0.001 and 0.004 respectively) with no significant difference between them as regards ferritin and copper levels (p value 0.7 and 0.6 respectively).

    Conclusions



    Children with attention deficit hyperactivity disorder had lower levels of zinc, ferritin and magnesium than healthy children but had normal copper levels.
     
  10. chocolate

    chocolate Silver

    http://www.ncbi.nlm.nih.gov/pubmed/21874320

    Ghrelin reduces voltage-gated calcium currents in GH₃ cells via cyclic GMP pathways.

    Han X, Zhu Y, Zhao Y, Chen C.

    Source



    Department of Physiology, Fourth Military Medical University, Shannxi, China.

    Abstract



    Ghrelin is an endogenous growth hormone secretagogue (GHS) causing release of GH from pituitary somatotropes through the GHS receptor. Secretion of GH is linked directly to intracellular free Ca2+ concentration ([Ca2+]i), which is determined by Ca2+ influx and release from intracellular Ca2+ storage sites. Ca2+ influx is via voltage-gated Ca2+ channels, which are activated by cell depolarization. The mechanism underlying the effect of ghrelin on voltage-gated Ca2+ channels is still not clear. In this report, using whole cell patch-clamp recordings, we assessed the acute action of ghrelin on voltage-activated Ca2+ currents in GH3 rat somatotrope cell line. Ca2+ currents were divided into three types (T, N, and L) through two different holding potentials (-80 and -40 mV) and specific L-type channel blocker (nifedipine, NFD). We demonstrated that ghrelin significantly and reversibly decreases all three types of Ca2+ currents in GH3 cells through GHS receptors on the cell membrane and down-stream signaling systems. With different signal pathway inhibitors, we observed that ghrelin-induced reduction in voltage-gated Ca2+ currents in GH3 cells was mediated by a protein kinase G-dependent pathways. As ghrelin also stimulates Ca2+ release and prolongs the membrane depolarization, this reduction in voltage-gated Ca2+ currents may not be translated into a reduction in [Ca2+]i, or a decrease in GH secretion.
     
  11. chocolate

    chocolate Silver

    https://www.bna.org.uk/news/view.php?permalink=BSY5JEXQSA

    Range of brain diseases could be treated by single drug



    10 May 2012 - The tantalising prospect of treating a range of brain diseases, such as Alzheimer's and Parkinson's, all with the same drug, has been raised by UK researchers.



    In a study, published in Nature, they prevented brain cells dying in mice with prion disease.



    It is hoped the same method for preventing brain cell death could apply in other diseases.



    The findings are at an early stage, but have been heralded as "fascinating".



    Many neuro-degenerative diseases result in the build-up of proteins which are not put together correctly - known as misfolded proteins. This happens in Alzheimer's, Parkinson's and Huntington's as well as in prion diseases, such as the human form of mad cow disease.



    Turn off



    Researchers at the University of Leicester uncovered how the build-up of proteins in mice with prion disease resulted in brain cells dying.



    They showed that as misfolded protein levels rise in the brain, cells respond by trying to shut down the production of all new proteins.



    It is the same trick cells use when infected with a virus. Stopping production of proteins stops the virus spreading. However, shutting down the factory for a long period of time ends up killing the brain cells as they do not produce the proteins they actually need to function.



    The team at the Medical Research Council laboratory in Leicester then tried to manipulate the switch which turned the protein factory off. When they prevented cells from shutting down, they prevented the brain dying. The mice then lived significantly longer.
     
  12. chocolate

    chocolate Silver

    http://www.psypost.org/2012/05/evolutions-gift-may-also-be-at-the-root-of-a-form-of-autism-11575

    Evolution’s gift may also be at the root of a form of autism



    share digg



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    Gene illustrationA recently evolved pattern of gene activity in the language and decision-making centers of the human brain is missing in a disorder associated with autism and learning disabilities, a new study by Yale University researchers shows.



    “This is the cost of being human,” said Nenad Sestan, associate professor of neurobiology, researcher at Yale’s Kavli Institute for Neuroscience, and senior author of the paper. “The same evolutionary mechanisms that may have gifted our species with amazing cognitive abilities have also made us more susceptible to psychiatric disorders such as autism.”



    The findings are reported in the May 11 issue of the journal Cell.



    In the Cell paper, Kenneth Kwan, the lead author, and other members of the Sestan laboratory identified the evolutionary changes that led the NOS1 gene to become active specifically in the parts of the developing human brain that form the adult centers for speech and language and decision-making. This pattern of NOS1 activity is controlled by a protein called FMRP and is missing in Fragile X syndrome, a disorder caused by a genetic defect on the X chromosome that disrupts FMRP production. Fragile X syndrome, the leading inherited form of intellectual disability, is also the most common single-gene cause of autism. The loss of NOS1 activity may contribute to some of the many cognitive deficits suffered by those with Fragile X syndrome, such as lower IQ, attention deficits, and speech and language delays, the authors say.
     
  13. chocolate

    chocolate Silver

    http://www.psypost.org/2012/05/brain-circuitry-is-different-for-women-with-anorexia-and-obesity-11662

    Brain circuitry is different for women with anorexia and obesity

    Why does one person become anorexic and another obese? A study recently published by a University of Colorado School of Medicine researcher shows that reward circuits in the brain are sensitized in anorexic women and desensitized in obese women. The findings also suggest that eating behavior is related to brain dopamine pathways involved in addictions.
     
  14. chocolate

    chocolate Silver

    http://discovermagazine.com/2012/jun/03-hidden-epidemic-tapeworms-in-the-brain

    Mind & Brain / Infectious Diseases

    The Brain Hidden Epidemic: 
Tapeworms Living Inside People's Brains



    Courtesy of Theodore E. Nash , M.D.



    Theodore Nash sees only a few dozen patients a year in his clinic at the National Institutes of Health in Bethesda, Maryland. That’s pretty small as medical practices go, but what his patients lack in number they make up for in the intensity of their symptoms. Some fall into comas. Some are paralyzed down one side of their body. Others can’t walk a straight line. Still others come to Nash partially blind, or with so much fluid in their brain that they need shunts implanted to relieve the pressure. Some lose the ability to speak; many fall into violent seizures.



    Underneath this panoply of symptoms is the same cause, captured in the MRI scans that Nash takes of his patients’ brains. Each brain contains one or more whitish blobs. You might guess that these are tumors. But Nash knows the blobs are not made of the patient’s own cells. They are tapeworms. Aliens.



    A blob in the brain is not the image most people have when someone mentions tapeworms. These parasitic worms are best known in their adult stage, when they live in people’s intestines and their ribbon-shaped bodies can grow as long as 21 feet. But that’s just one stage in the animal’s life cycle. Before they become adults, tapeworms spend time as larvae in large cysts. And those cysts can end up in people’s brains, causing a disease known as neurocysticercosis.



    I wonder how those worms like the 32 degree water?
     
  15. chocolate

    chocolate Silver

    http://www.psypost.org/2012/05/neuron-nourishing-cells-appear-to-retaliate-in-alzheimers-disease-11819

    Neuron-nourishing cells appear to retaliate in Alzheimer’s disease



     
  16. chocolate

    chocolate Silver

    http://www.psypost.org/2012/05/persistent-sensory-experience-is-good-for-the-ageing-brain-11913

    Persistent sensory experience is good for the ageing brain

    “This study overturns decades-old beliefs that most of the brain is hard-wired before a critical period that ends when one is a young adult,” said MPFI neuroscientist Marcel Oberlaender, PhD, first author on the paper. “By changing the nature of sensory experience, we were able to demonstrate that the brain can rewire, even at an advanced age. This may suggest that if one stops learning and experiencing new things as one ages, a substantial amount of connections within the brain may be lost.”



    The researchers conducted their study by examining the brains of older rats, focusing on an area of the brain known as the thalamus, which processes and delivers information obtained from sensory organs to the cerebral cortex. Connections between the thalamus and the cortex have been thought to stop changing by early adulthood, but this was not found to be the case in the rodents studied.



    Being nocturnal animals, rats mainly rely on their whiskers as active sensory organs to explore and navigate their environment. For this reason, the whisker system is an ideal model for studying whether the brain can be remodelled by changing sensory experience. By simply trimming the whiskers, and preventing the rats from receiving this important and frequent form of sensory input, the scientists sought to determine whether extensive rewiring of the connections between the thalamus and cortex would occur.



    On examination, they found that the animals with trimmed whiskers had altered axons, nerve fibres along which information is conveyed from one neuron (nerve cell) to many others; those whose whiskers were not trimmed had no axonal changes. Their findings were particularly striking as the rats were considered relatively old – meaning that this rewiring can still take place at an age not previously thought possible. Also notable was that the rewiring happened rapidly – in as little as a few days.



    “We’ve shown that the structure of the rodent brain is in constant flux, and that this rewiring is shaped by sensory experience and interaction with the environment,” said Oberlaender. “These changes seem to be life-long and may pertain to other sensory systems and species, including people. Our findings open the possibility of new avenues of research on development of the aging brain using quantitative anatomical studies combined with noninvasive imaging technologies suitable for humans, such as functional MRI (fMRI).”



    The study was possible due to recent advances in high-resolution imaging and reconstruction techniques, developed in part by Oberlaender at MPFI. These novel methods enable researchers to automatically and reliably trace the fine and complex branching patterns of individual axons, with typical diameters less than a thousandth of a millimetre, throughout the entire brain.



    Oberlaender is part of the Max Planck Florida Institute’s Digital Neuroanatomy group, led by Nobel laureate Bert Sakmann. The group focuses on the functional anatomy of circuits in the cerebral cortex that form the basis of simple behaviours (e.g. decision making). One of the group’s most significant efforts is a program dedicated to obtaining a three-dimensional map of the rodent brain. This work will provide insight into the functional architecture of entire cortical areas, and will lay the foundation for a mechanistic understanding of sensory perception and behaviour.
     
  17. AKMan

    AKMan New Member

    I love these links you posted here! Thanks for taking the time and putting a small excerpt from the link as a preview. I know it takes some time, but it is much more helpful than just posting a link.



    Have you ever looked at http://medicalxpress.com/ ? It's an off-shoot of physorg and full f current studies/papers.



    Cheers!
     
  18. chocolate

    chocolate Silver

    http://www.psypost.org/2012/05/ketamine-improves-bipolar-depression-within-minutes-11941

    Ketamine improves bipolar depression within minutes



    Bipolar disorder is a serious and debilitating condition where individuals experience severe swings in mood between mania and depression. The episodes of low or elevated mood can last days or months, and the risk of suicide is high.



    Antidepressants are commonly prescribed to treat or prevent the depressive episodes, but they are not universally effective. Many patients still continue to experience periods of depression even while being treated, and many patients must try several different types of antidepressants before finding one that works for them. In addition, it may take several weeks of treatment before a patient begins to feel relief from the drug’s effects.



    For these reasons, better treatments for depression are desperately needed. A new study in Biological Psychiatry this week confirms that scientists may have found one in a drug called ketamine.



    A group of researchers at the National Institute of Mental Health, led by Dr. Carlos Zarate, previously found that a single dose of ketamine produced rapid antidepressant effects in depressed patients with bipolar disorder. They have now replicated that finding in an independent group of depressed patients, also with bipolar disorder. Replication is an important component of the scientific method, as it helps ensure that the initial finding wasn’t accidental and can be repeated.

    In this new study, they administered a single dose of ketamine and a single dose of placebo to a group of patients on two different days, two weeks apart. The patients were then carefully monitored and repeatedly completed ratings to ‘score’ their depressive symptoms and suicidal thoughts.



    When the patients received ketamine, their depression symptoms significantly improved within 40 minutes, and remained improved over 3 days. Overall, 79% of the patients improved with ketamine, but 0% reported improvement when they received placebo.



    Importantly, and for the first time in a group of patients with bipolar depression, they also found that ketamine significantly reduced suicidal thoughts. These antisuicidal effects also occurred within one hour. Considering that bipolar disorder is one of the most lethal of all psychiatric disorders, these study findings could have a major impact on public health.
     
  19. chocolate

    chocolate Silver

    http://www.psypost.org/2012/06/alzheimers-protein-structure-suggests-new-treatment-directions-11996

    Alzheimer’s protein structure suggests new treatment directions

    The molecular structure of a protein involved in Alzheimer’s disease – and the surprising discovery that it binds cholesterol – could lead to new therapeutics for the disease, Vanderbilt University investigators report in the June 1 issue of the journal Science.



    Charles Sanders, Ph.D., professor of Biochemistry, and colleagues in the Center for Structural Biology determined the structure of part of the amyloid precursor protein (APP) – the source of amyloid-beta, which is believed to trigger Alzheimer’s disease. Amyloid-beta clumps together into oligomers that kill neurons, causing dementia and memory loss. The amyloid-beta oligomers eventually form plaques in the brain – one of the hallmarks of the disease.



    “Anything that lowers amyloid-beta production should help prevent, or possibly treat, Alzheimer’s disease,” Sanders said.



    share digg



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    Image by Charles Sanders and colleagues at Vanderbilt UniversityThe molecular structure of a protein involved in Alzheimer’s disease – and the surprising discovery that it binds cholesterol – could lead to new therapeutics for the disease, Vanderbilt University investigators report in the June 1 issue of the journal Science.



    Charles Sanders, Ph.D., professor of Biochemistry, and colleagues in the Center for Structural Biology determined the structure of part of the amyloid precursor protein (APP) – the source of amyloid-beta, which is believed to trigger Alzheimer’s disease. Amyloid-beta clumps together into oligomers that kill neurons, causing dementia and memory loss. The amyloid-beta oligomers eventually form plaques in the brain – one of the hallmarks of the disease.



    “Anything that lowers amyloid-beta production should help prevent, or possibly treat, Alzheimer’s disease,” Sanders said.



    Amyloid-beta production requires two “cuts” of the APP protein. The first cut, by the enzyme beta-secretase, generates the C99 protein, which is then cut by gamma-secretase to release amyloid-beta. The Vanderbilt researchers used nuclear magnetic resonance and electron paragmagnetic resonance spectroscopy to determine the structure of C99, which has one membrane-spanning region.



    They were surprised to discover what appeared to be a “binding” domain in the protein. Based on previously reported evidence that cholesterol promotes Alzheimer’s disease, they suspected that cholesterol might be the binding partner. The researchers used a model membrane system called “bicelles” (that Sanders developed as a postdoctoral fellow) to demonstrate that C99 binds cholesterol.



    “It has long been thought that cholesterol somehow promotes Alzheimer’s disease, but the mechanisms haven’t been clear,” Sanders said. “Cholesterol binding to APP and its C99 fragment is probably one of the ways it makes the disease more likely.”



    Sanders and his team propose that cholesterol binding moves APP to special regions of the cell membrane called “lipid rafts,” which contain “cliques of molecules that like to hang out together,” he said.



    Beta- and gamma-secretase are part of the lipid raft clique.

    “We think that when APP doesn’t have cholesterol around, it doesn’t care what part of the membrane it’s in,” Sanders said. “But when it binds cholesterol, that drives it to lipid rafts, where these ‘bad’ secretases are waiting to clip it and produce amyloid-beta.”



    The findings suggest a new therapeutic strategy to reduce amyloid-beta production, he said.



    “If you could develop a drug that blocks cholesterol from binding to APP, then you would keep the protein from going to lipid rafts. Instead it would be cleaved by alpha-secretase – a ‘good’ secretase that isn’t in rafts and doesn’t generate amyloid-beta.”



    Drugs that inhibit beta- or gamma-secretase – to directly limit amyloid-beta production – have been developed and tested, but they have toxic side effects. A drug that blocks cholesterol binding to APP may be more specific and effective in reducing amyloid-beta levels and in preventing, or treating, Alzheimer’s disease.



    The C99 structure had some other interesting details, Sanders said.



    The membrane domain of C99 is curved, which was unexpected but fits perfectly into the predicted active site of gamma-secretase. Also, a certain sequence of amino acids (GXXXG) that usually promotes membrane protein dimerization (two of the same proteins interacting with each other) turned out to be central to the cholesterol-binding domain. This is a completely new function for GXXXG motifs, Sanders said.

    “This revealing new information on the structure of the amyloid precursor protein and its interaction with cholesterol is a perfect example of the power of team science,” said Janna Wehrle, Ph.D., who oversees grants focused on the biophysical properties of proteins at the National Institutes of Health’s National Institute of General Medical Sciences (NIGMS), which partially funded the work. “The researchers at Vanderbilt brought together biological and medical insight, cutting-edge physical techniques and powerful instruments, each providing a valuable tool for piecing together the puzzle.”



    Sanders is proud that the studies reflect the value of basic science research and the full continuum of basic to clinical science.



    “When we were developing bicelles 20 years ago, no one was saying, ‘someday these things are going to lead to discoveries in Alzheimer’s disease,’” he said. “It was interesting basic science research that is now paying off.”
     
  20. skline@peak.org

    skline@peak.org New Member


    Black caps can be blackberries, but in this particular case, blackcaps are birds -- nice little warblers. I just Googled the species name they gave.



    http://en.wikipedia.org/wiki/Blackcap



    Chocolate, you are a force of nature! Keep the cites coming!!
     

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