(Press-News.org) This news release is available in French.
We have known for some years that Alzheimer's disease is characterised by two types of lesions, amyloid plaques and degenerated tau protein. Cholesterol plays an important role in the physiopathology of this disease. Two French research teams (Inserm/CEA/University of Lille/University of Paris-Sud ) have just shown, in a rodent model, that overexpressing an enzyme that can eliminate excess cholesterol from the brain may have a beneficial action on the tau component of the disease, and completely correct it. This is the first time that a direct relationship has been shown between the tau component of Alzheimer's disease and cholesterol. This work is published in the 10 September 2015 issue of Human Molecular Genetics.
Excess brain cholesterol cannot freely cross the blood-brain barrier; to be eliminated it must be converted into 24-hydroxycholesterol (24-OHC) by the enzyme CYP46A1 (cholesterol-24-hydroxylase). At Inserm Unit 1169, Nathalie, Cartier, coordinator of this work, and Patrick Aubourg, director of the unit, proposed the hypothesis that increasing the efflux of cholesterol from the brain by overexpressing CYP46A1 might have a beneficial effect on the elements of Alzheimer pathology.
The first step in this work made it possible to show that injecting a viral vector, AAV-CYP46A1, effectively corrects a mouse model of amyloid pathology of the disease, the APP23 mouse. CYP46A1 thus appears to be a therapeutic target for Alzheimer's disease.
Conversely, in vivo inhibition of CYP46A1 in the mice, using antisense RNA molecules delivered by an AAV vector administered to the hippocampus, induces an increase in the production of Aß peptides, abnormal tau protein, neuronal death and hippocampal atrophy, leading to memory problems. Together these elements reproduce a phenotype mimicking Alzheimer's disease.
These results demonstrate the key role of cholesterol in the disease, and confirm the relevance of CYP46A1 as a potential therapeutic target (work published in Brain on 3 July 2015).
Taken together, this work now enables the research team coordinated by Nathalie Cartier, Inserm Research Director, to propose a gene therapy approach for Alzheimer's disease: intracerebral administration of a vector, AAV-CYP46A1, in patients with early and severe forms (1% of patients, familial forms) for whom there is no available treatment.
"To achieve this objective, we are carrying out all the preclinical steps of development and validation of the tools (vector, neurosurgical protocol, elements of monitoring) for demonstrating the efficacy and tolerance of the strategy, in order to submit an application for authorisation of a clinical trial," explains Nathalie Cartier.
This project is supported by the French Medical Research Foundation (FRM; Bioengineering for Health programme), and by Fondation France Alzheimer.
CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease
F Djelti, J Braudeau, E Hudry, M Dhenain, J Varin, I Bièche, C Marquer, F Chali, S Ayciriex, N Auzeil, S Alves, D Langui, MC Potier, O Laprevote, M Vidaud, C Duyckaerts, R Miles, P Aubourg and N Cartier
Brain, 3 July 2015
Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like tau pathology
Marie-Anne Burlot, Jerome Braudeau, Kristin Michaelsen-Preusse, Brigitte Potier, Sophie Ayciriex, Jennifer Varin, Benoit Gautier, Fathia Djelti, Mickael Audrain, Luce Dauphinot, Francisco-Jose Fernandez-Gomez, Raphaelle Caillierez, Olivier Laprevote, Ivan Bi.che, Nicolas Auzeil, Marie-Claude Potier, Patrick Dutar, Martin Korte, Luc Buée, David Blum and Nathalie Cartier
Hum Mol Genetics, 10 September 2015
Inserm Research Director
Inserm Unit 1169, "Gene Therapy, Genetics and Epigenetics in Neurology, Endocrinology and Child Development" (Inserm/CEA/University of Paris-Sud)
33 (0)1 46 54 93 91
Access the Inserm press room: presse-inserm.fr/en/
The press release in English: http://presse-inserm.fr/en/modulation-of-brain-cholesterol-a-new-line-of-research-in-alzheimers-disease-treatment/20572/
In French : http://presse-inserm.fr/moduler-le-cholesterol-cerebral-une-nouvelle-piste-de-recherche-pour-traiter-la-maladie-dalzheimer/20572/
WASHINGTON, Sept. 14, 2015 -- It's a condition that turns the lives of millions of Americans upside-down: addiction. Whether it's alcohol, drugs, food or gambling, it can ruin lives. In support of National Recovery Month, which calls attention to substance abuse issues and treatment services, Reactions takes a look at the chemistry behind addiction. Check it out here: https://youtu.be/C6I3CHhBGeQ.
Subscribe to the series at http://bit.ly/ACSReactions, and follow us on Twitter @ACSreactions to be the first to see our latest videos.
INFORMATION:The American Chemical ...
DURHAM, N.C. -- Protected areas not only keep significant swaths of Indonesia's shrinking mangrove habitats intact, but also prevent emissions of carbon dioxide that would have been released had these mangroves been cleared, according to a study in the journal Ecological Economics.
Published online, the analysis examined the success of protected areas between 2000 and 2010, finding that their use has avoided the loss of 14,000 hectares of mangrove habitat.
"This is not a small number," said Daniela Miteva, a postdoctoral researcher at The Nature Conservancy and a Duke ...
Whether you have taken a side or a backseat in the discussion, the "food versus fuel" debate affects us all. Some say growing more biofuel crops today will decrease greenhouse gas emissions, but will make it harder to produce food tomorrow, which has prevented the U.S. from maximizing the potential of environmentally beneficial biofuels.
In a recent article, published by the National Academy of Engineering, University of Illinois' Gutgsell Endowed Chair of Plant Biology and Crop Sciences Steve Long and University of California's Philomathia Professor of Alternative Energy ...
University of Queensland scientists have found a genetic basis for height and body mass differences between European populations.
Queensland Brain Institute researcher Dr Matthew Robinson said the findings could explain why people from northern European countries tended on average to be taller and slimmer than other Europeans.
He said the genes that resulted in greater height correlated strongly with genes that reduced body mass index.
"Our findings give a genetic basis to the stereotype of Scandinavians as being tall and lean," Dr Robinson said.
The study paves ...
Researchers at the Johns Hopkins University have found molecular evidence of how a biochemical process controls the lengths of protective chromosome tips, a potentially significant step in ultimately understanding cancer growth and aging.
In a paper recently published as the cover story in the online journal eLife, biologist David C. Zappulla and graduate student Evan P. Hass show how in baker's yeast cells, two proteins work together to usher a key enzyme to the chromosome tip, the telomere, to restore its length, which diminishes with each round of cell division.
A new study from researchers at Uppsala University shows that variation in genome size may be much more important than previously believed. It is clear that, at least sometimes, a large genome is a good genome.
'Our study shows that females with larger genome lay more eggs and males with larger genome fertilize more eggs', says research leader Göran Arnqvist, Professor of Animal Ecology at Uppsala University.
The study of seed beetles is published in the scientific journal Proceedings of the Royal Society of London.
The amount of nuclear DNA per cell, or the ...
Philadelphia, PA, September 14, 2015 - One in four middle-aged adults who survive to age 85 will develop heart failure, according to current estimates. Intervention programs to improve lifestyles are widely advocated, but do they actually work? Investigators in the U.S. and Taiwan independently examined programs that may reduce cardiovascular risk and concluded that both programs will reduce lifetime risk of heart failure. Results are reported in The American Journal of Medicine.
A group of American investigators estimated whether greater adherence to the American Heart ...
Philadelphia, PA, September 14, 2015 - The latest issue of Biological Psychiatry presents the results of three studies implicating metabotropic glutamate receptor 2 (mGluR2) as a new molecular target for the treatment of addiction.
Group II metabotropic glutamate receptors, which include the subtypes mGluR2 and mGluR3, have been known targets for addiction treatment. Unfortunately, mGluR2/3 agonists studied to date have shown important limitations, including development of tolerance and decreasing food intake along with drug intake. Thus, scientists have been working ...
This news release is available in German. FRANKFURT. Optogenetics is a quickly expanding field of research which has revolutionized neurobiological and cellbiological research around the world. It uses natural or tailored light-sensitive proteins in order to switch nerve cells on and off without electrodes with unprecedented accuracy in respect to time and location. The discovery of the light-gated ion channel channelrhodopsin in algae in 2002 was a key finding for this field. In 2005, Frankfurt scientists working with Prof. Alexander Gottschalk succeeded in transferring ...
COLUMBUS, Ohio--The next time someone accuses you of making an irrational decision, just explain that you're obeying the laws of quantum physics.
A new trend taking shape in psychological science not only uses quantum physics to explain humans' (sometimes) paradoxical thinking, but may also help researchers resolve certain contradictions among the results of previous psychological studies.
According to Zheng Joyce Wang and others who try to model our decision-making processes mathematically, the equations and axioms that most closely match human behavior may be ones ...