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PMID: 17760499 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Reducing amyloid plaque burden via ex vivo gene delivery of an Abeta-degrading protease: a novel therapeutic approach to Alzheimer disease.

PLoS medicine ·Vol. 4 ·No. 8 ·2007-08-00 ·Pages e262

Hemming ML, Patterson M, Reske-Nielsen C, Lin L, Isacson O, Selkoe DJ

Abstract

Understanding the mechanisms of amyloid-beta protein (Abeta) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Abeta levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Abeta in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Abeta levels in AD. The objective of this study was to determine if enhancing the clearance of Abeta in the brain by ex vivo gene delivery of an Abeta-degrading protease can reduce amyloid plaque burden. We generated a secreted form of the Abeta-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Abeta in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of beta-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively). Ex vivo gene delivery of an Abeta-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Abeta-degrading proteases as a means to therapeutically lower Abeta levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.

MeSH Terms
Alzheimer Disease/genetics,metabolism,therapy Amyloid beta-Peptides/metabolism Animals CHO Cells Cell Line Cells, Cultured Cricetinae Cricetulus Enzyme-Linked Immunosorbent Assay Genetic Therapy/methods Genetic Vectors/genetics Gliosis/genetics Humans Immunoblotting Immunohistochemistry Mice Mice, Inbred C57BL Mice, Transgenic Neprilysin/genetics,metabolism Plaque, Amyloid/metabolism Transfection Transplants
Chemicals
Amyloid beta-Peptides Neprilysin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Hemming Matthew L
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Patterson Michaela
Reske-Nielsen Casper
Lin Ling
Isacson Ole
Selkoe Dennis J
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Article Info
Journal
PLoS medicine
Abbr.
PLoS Med
ISSN
1549-1676
DOI
10.1371/journal.pmed.0040262
Published
2007-08-00
Pages
e262
Language
English
Region
United States
NLM ID
101231360
PMCID
PMC1952204
Subset
IM
Grants
NINDS NIH HHS · P50 NS039793 · United States
NIA NIH HHS · R01 AG012749 · United States
NIA NIH HHS · AG12749 · United States
NINDS NIH HHS · NS39793 · United States
External Links
PubMed source DOI: 10.1371/journal.pmed.0040262 PMC Full Text View journal details
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