They have synthesized and tested more than 1, compounds for their ability to specifically bind and inhibit QC and isoQC, and are identifying promising candidates. Demuth said he hopes for Phase 1 trials next year. Similar results were obtained in 3xTg AD mice , as described in a poster by first author Qiaoqiao Shi. The researchers are now testing prevention by means of passive immunization in younger AD mice, as well as examining the effects of active immunization in J20 mice. Move over, mice. At the Society for Neuroscience annual meeting, held November in San Diego, California, researchers learned about canines with idiopathic laryngeal paralysis ILP , a disease that looks suspiciously similar to bulbar-onset ALS.
If that is confirmed, these animals will join a group of dogs with degenerative myelopathy DM , which share a genetic mutation with the human version of the disease. These animals suffer problems in swallowing that mirror the bulbar onset in one-quarter of people who get ALS. There is no real animal model for bulbar-onset ALS, said Bob Brown of the University of Massachusetts in Worcester, although some mice may exhibit symptoms in the neck area.
Thus far, Stanley has been unable to find a genetic cause for the ILP. Dog models offer many advantages. Thus, they may be exposed to the same toxins that some researchers suspect contribute to ALS.
Because owners choose to euthanize their pets at different stages, dogs offer the opportunity to examine disease pathology before end-stage, which is impossible in people. Dogs have less well-shuffled genomes than do people, he said, so their linkage disequilibrium groups are large, and scientists can find gene associations with a relatively small sample. Degeneration of the laryngeal nerves leads to paralysis of the laryngeal muscles, and symptoms include gagging, throat clearing, and a raspy or hoarse-sounding bark.objectifcoaching.com/components/journal/rencontres-ath.php
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Dogs tend to get sick around 10 years of age, and generally last for one to three years longer, Stanley told ARF. Stanley and colleagues followed dogs with ILP for a year and performed neurological tests, looking at gait, muscle tone, and reflexes see Stanley et al. Of 32 dogs with ILP, 10 had neurologic problems when they enrolled in the study. Half of the dogs had them by six months, and all had neurological signs within a year of enrollment.
Eventually, the dogs with ILP became paralyzed. In comparison, none of the 34 control dogs showed neurological symptoms. Stanley is working to further characterize ILP, and recruited Michigan State neuropathologist Howard Chang to help analyze tissue samples. So far, she has had no hits, and plans to continue the search with a GWAS.
Dog Genes The University of Missouri researchers do have a genetic link for degenerative myelopathy. This is an advantage, Gubitz said, because research colonies can be bred.
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Indeed, the scientists have already begun a proof-of-concept study of ALS treatment in bred-for-research animals, Coates told ARF, although she said it is too early to reveal any details. Coates and colleagues first studied DM, which has its onset in the hind limbs, in Pembroke Welsh corgies and boxers. At least 17 breeds can get the disease, and more than two dozen breeds carry the missense SOD1 allele at a frequency greater than 20 percent. Most of the dogs have the same missense mutation—E40K—although the scientists may have found a second SOD1 mutation in one Bernese mountain dog, Coates said.
That is not true in dogs, where few heterozygotes get sick and some homozygotes escape disease. This incomplete penetrance, Coates suggested, may be because some dogs die before the disease has time to develop. If that is true, she thinks there must be genetic factors that enhance or reduce risk. The researchers are conducting a GWAS to find those risk factors. Coates and colleagues are also interested in finding biomarkers that would allow them to follow disease progression.
Using electronic stimulation and recording, MUNE tells the scientists how many neuromuscular junctions a particular muscle has. She counted axon fibers in cross-sections from T8 vertebra motor roots.
Society for Neuroscience Annual Meeting 2010
Two healthy boxers had an average of 5, axons. But in seven boxers with DM, Morgan discovered an average of 4, axons. This reduction in fiber count is similar to ALS pathology. Given the heterogeneity of ALS in people, it is unlikely that any single model will be the only one used in research, Gubitz said. Instead, she envisions a panel of models that researchers will use in parallel.
Dogs just might be on the list.
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Strong epidemiological evidence suggests diabetes is a risk factor for AD, but capitalizing on that connection has not been plain sailing. While there is some early hint that intranasal insulin might offer some protection against dementia, sensitizing agents such as pio- and rosiglitazone failed to pass muster in larger clinical trials for dementia ARF related news story. Could it be time for a new tack? At the 40th annual meeting of the Society for Neuroscience SfN , held November in San Diego, the promise of glucagon-like peptide agonists seemed to breathe new life into insulin signaling as a therapeutic target.
Because of new human and animal model data, it appears the field might see several clinical trials testing this drug class in the coming year, according to researchers.
Just what are those insulin signaling deficits that crop up in AD? Insulin binds to cell surface receptors, kicking off a signaling cascade that relies on a number of kinases, commonly including phosphoinositolkinase PI3K and Akt see ARF related news story. At the SfN meeting, Talbot and Hoau-Yan Wang , City University of New York Medical School, reported on their collaborative work to examine the activation status of this pathway in the brain at baseline, and following insulin stimulation. The researchers used immunohistochemistry to look for phosphorylated epitopes in early postmortem tissue taken from normal controls, people with MCI, and people with AD.
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The most prominent AD feature was serine phosphorylation of insulin receptor substrate 1 IRS-1 , which helps propagate signals from the insulin receptor to downstream kinases. The phosphorylation, of serines , , and especially , was mostly extranuclear, which is unusual. Serine phosphorylation of these sites is inhibitory, Talbot explained, and in keeping with this, he saw reduced activation of IRS The levels of S phosphorylation were also markedly elevated in MCI patients but not in tissue from normal controls or people with other forms of dementia.
Furthermore, the density of neurons containing extranuclear, serine-phosphorylated IRS-1 correlated with elevated oligomeric plaque load and deficits in global cognition, working memory, and especially episodic memory, that last having a tight correlation R value of 0. After the researchers adjusted for a variety of cofactors, including age, sex, years of education, density of neurofibrillary tangles, and oligomeric plaque load, the number of cells with inactivated IRS-1 still correlated with cognition, which suggests that dysfunctional insulin signaling is related to whatever is causing memory problems, said Talbot.
In contrast, correlations between oligomeric plaque load and cognition disappeared when corrected for serine-phosphorylated IRS Talbot collaborated with Wang, an expert in ex-vivo analysis, to study the ability of brain tissue to respond to insulin. They took early postmortem hippocampal tissue samples from six age-matched pairs—normal and AD—incubated them with low concentrations 1 and 10 nM of insulin to stimulate insulin but not insulin-like growth factor receptors , then looked for downstream effects.
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This ex-vivo analysis revealed a blunted insulin response in AD tissue. Tyrosine phosphorylation activation of IRS-1 was impaired. The AD tissue samples mounted a lackluster activation of a variety of downstream kinases, as judged by phospho-epitope analysis. Phosphorylation of Akt serine , mTOR serine , and ERK2 tyrosine were all significantly lower than in normal tissue treated with insulin.
Curiously though, baseline levels of these phospho-epitopes were higher in AD tissue, which could reflect an attempt to compensate for impaired insulin signaling. What causes dysfunctional insulin signaling in AD, and could correcting it help? These post-translational modifications are also found in muscle and adipose tissue in diabetes patients, said De Felice. Holscher briefly reviewed some of the properties of GLP-1 and its mimics. These molecules increase insulin sensitivity by facilitating insulin release and re-sensitizing insulin receptors. They act in the brain, where neurons, particularly pyramidal neurons of the cortex and hippocampus, express GLP-1 and its receptors.
The peptide has neurotrophic properties, boosting synaptic transmission and neuronal progenitors. Liraglutide also dramatically boosted LTP in anesthetized animals, said Holscher.
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Paired pulse facilitation, another correlate of learning, also improved. Perhaps the most surprising effect of these agonists is on amyloid plaques. After the eight-week liraglutide treatment, plaque density was half that in untreated animals and the number of dense core plaques fell by two-thirds. Whether this also happens in vivo needs to be tested, he said. Could trials in AD soon follow? Across the pond, Holscher has been in discussions with colleagues at Hammersmith Hospital, London, to put forward a plan for a clinical trial of liraglutide.
He noted that since exendin-4 and liraglutide have different pharmacological properties, trials of both are warranted. But despite decades of research, it is still not clear how it ties in with AD etiology. ApoE is a lipid transport protein, and brain areas involved in learning and memory, which show heavy amyloid deposition in AD, also express abundant receptors for ApoE and other lipoproteins.
Robert Koffie , an M.