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Scientific result | Alzheimer's disease | Gene and cell therapy | Biotechnology
It has been known since several years that Alzheimer's disease is characterized by two lesions: amyloid plaques and the degeneration of tau protein. Cholesterol plays an important role in the pathophysiology of this disease. Two French research teams (INSERM/CEA/Université de Lille/Université Paris-Sud) have recently shown in a rodent model that overexpression of an enzyme capable of eliminating excess cholesterol in the brain can act in a beneficial way on the tau component of the disease to completely correct it. This is the first time that a direct link has been shown between the tau component of Alzheimer's disease and cholesterol. This work was published in the journal Human Molecular Genetics on September 10, 2015.
Excess cerebral cholesterol cannot freely cross the blood-brain barrier; to be removed, it must be converted by the enzyme CYP46A1 (cholesterol-24-hydroxylase) into 24-hydroxy-cholesterol (24-OHC). Within the INSERM 1169 unit, Nathalie Cartier, coordinator of this work, and Patrick Aubourg, director of the unit, speculated that increasing the cholesterol efflux out of the brain by overexpressing the enzyme CYP46A1 could have a beneficial effect on elements of the Alzheimer pathology. The first step of this work made it possible to show that injecting the viral vector AAV-CYP46A1 effectively corrects the disease's amyloid pathology in the mouse model APP23. The enzyme CYP46A1 thus appeared as a therapeutic target for Alzheimer's disease. In contrast, the
in vivo inhibition of this enzyme in mice by using anti-sense RNA molecules supplied by an AAV vector administered in the hippocampus induces the increased production of Aß peptides, abnormal tau, neuronal death and hippocampal atrophy responsible for memory disorders. Altogether, they reproduce a phenotype mimicking the Alzheimer pathology. These results demonstrate the key role of cholesterol in the pathology, and confirm the relevance of the enzyme CYP46A1 as a potential therapeutic target (this work was published on July 3, 2015 in the journal Brain). Today, the ensemble of these works allows the research team coordinated by Nathalie Cartier, director of research at INSERM, to propose a gene therapy approach for Alzheimer's disease: the intracerebral administration of an AAV-CYP46A1 vector in patients with early and severe forms (1% of patients, hereditary forms) for which no treatment is available.
The teams involved in this publication are: the team of David Blum and Luc Buée (Centre de recherche Jean-Pierre Aubert Unité INSERM 1172/Université Lille/CHRU) and the team of Nathalie Cartier, INSERM Research Director (INSERM Unit 1169 "Therapie genique, genetique, epigenetique en neurologie, endocrinologie et développement de l'enfant", Université Paris Sud, CEA, Paris) based at MIRCen (Molecular Imaging Research Center), a preclinical research facility at the CEA center of Fontenay aux-Roses .
"To achieve this goal, we undertook all of the pre-clinical stages of development and validation of tools (vector, neurosurgical protocol, and monitoring elements) to demonstrate the efficacy and tolerance of the strategy, in order to apply for clinical trial authorization in the medium term", explains Nathalie Cartier.
This project is supported by the Fondation pour la Recherche Médicale (Bioengineering for Health) and the Fondation France Alzheimer.
Cholesterol-24-hydroxylase (CYP46a1) inhibition and accumulation of neuronal cholesterol in hippocampus leads to amyloid production, neurodegeneration and paves 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, N Cartier -
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, Nathalie Cartier -
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.