Adeno-associated viral (AAV) serotype 5 vector mediated gene delivery of endothelin-converting enzyme reduces Abeta deposits in APP + PS1 transgenic mice.
Reduction of Abeta deposition is a major therapeutic strategy in Alzheimer's disease (AD). The concentration of Abeta in the brain is modulated not only by Abeta production but also by its degradation. One of the proteases involved in the degradation of Abeta peptides is endothelin-converting enzyme (ECE). In this study, we investigated the effects of an intracranial administration of a seroptype 5 recombinant adeno-associated viral vector (rAAV) containing the ECE-1 synthetic gene on amyloid deposition in amyloid precursor protein (APP) plus presenilin-1 (PS1) transgenic mice. The rAAV vector was injected unilaterally into the right anterior cortex and hippocampus of 6-month-old mice, while control mice received an AAV vector expressing green fluorescent protein (GFP). Immunohistochemical testing for the hemagglutinin (HA) tag appended to ECE revealed strong expression in areas surrounding the injection sites but minimal expression in the contralateral regions. Immunohistochemical tests showed that Abeta decreases in the anterior cortex and hippocampus in mice receiving the ECE synthetic gene. Further, decreases in Congo red positive deposits were also observed in both regions. These results indicate that increasing the expression of beta-amyloid degrading enzymes through gene therapy is a promising approach to the treatment of AD.
Carty
Niki C
NC
Alzheimer's Research Laboratory, Department of Molecular Pharmacology and Physiology, School of Biomedical Sciences, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
Nash
Kevin
K
Lee
Daniel
D
Mercer
Mary
M
Gottschall
Paul E
PE
Meyers
Craig
C
Muzyczka
Nicholas
N
Gordon
Marcia N
MN
Morgan
Dave
D
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D015153:Blotting, Western; D000229:Dependovirus / Q000235:genetics*; D000072396:Endothelin-Converting Enzymes; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000378:metabolism*
D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes