Adeno-associated Virus Gene Therapy With Cholesterol 24-Hydroxylase Reduces the Amyloid Pathology Before or After the Onset of Amyloid Plaques in Mouse Models of Alzheimer's Disease

• Published in: Molecular therapy Vol. 18; no. 1; pp. 44 - 53
• Main Authors: Hudry, Eloise, Van Dam, Debby, Kulik, Wim, De Deyn, Peter P, Stet, Femke S, Ahouansou, Ornella, Benraiss, Abdellatif, Delacourte, André, Bougnères, Pierre, Aubourg, Patrick, Cartier, Nathalie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2010; Elsevier Limited; Nature Publishing Group
• Subjects: Age; Alzheimer Disease - metabolism; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid - metabolism; Animals; Blotting, Western; Brain; Cell Line; Cholesterol; Cholesterol 24-Hydroxylase; Dependovirus - genetics; Disease; Enzyme-Linked Immunosorbent Assay; Enzymes; Gene therapy; Genetic Therapy - methods; Homeostasis; Humans; Hydroxycholesterols - metabolism; Immunohistochemistry; Metabolism; Mice; Mice, Transgenic; Original; Pathology; Peptides; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Steroid Hydroxylases - genetics; Steroid Hydroxylases - physiology; Belgium; France; Paris France
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2009.175

The development of Alzheimer's disease (AD) is closely connected with cholesterol metabolism. Cholesterol increases the production and deposition of amyloid-β (Aβ) peptides that result in the formation of amyloid plaques, a hallmark of the pathology. In the brain, cholesterol is synthesized in situ but cannot be degraded nor cross the blood–brain barrier. The major exportable form of brain cholesterol is 24S-hydroxycholesterol, an oxysterol generated by the neuronal cholesterol 24-hydroxylase encoded by the CYP46A1 gene. We report that the injection of adeno-associated vector (AAV) encoding CYP46A1 in the cortex and hippocampus of APP23 mice before the onset of amyloid deposits markedly reduces Aβ peptides, amyloid deposits and trimeric oligomers at 12 months of age. The Morris water maze (MWM) procedure also demonstrated improvement of spatial memory at 6 months, before the onset of amyloid deposits. AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 (APP/PS) mice after the onset of amyloid deposits also reduced markedly the number of amyloid plaques in the hippocampus, and to a less extent in the cortex, 3 months after the injection. Our data demonstrate that neuronal overexpression of CYP46A1 before or after the onset of amyloid plaques significantly reduces Aβ pathology in mouse models of AD.