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AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.

Abstract
Accumulation of aggregated amyloid-beta (Abeta) peptide was studied as an initial step for Alzheimer's disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of chemokine CCL2 in the brain results in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose-response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, beta-amyloidosis, including suppression of both fibrillar and oligomer Abeta accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.
AuthorsTomomi Kiyota, Masaru Yamamoto, Bryce Schroder, Michael T Jacobsen, Russell J Swan, Mary P Lambert, William L Klein, Howard E Gendelman, Richard M Ransohoff, Tsuneya Ikezu
JournalMolecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 17 Issue 5 Pg. 803-9 (May 2009) ISSN: 1525-0024 [Electronic] United States
PMID19277012 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Chemokine CCL2
  • Presenilin-1
Topics
  • Amyloid beta-Peptides (metabolism)
  • Amyloid beta-Protein Precursor (genetics)
  • Amyloidosis (therapy)
  • Animals
  • Chemokine CCL2 (genetics, physiology)
  • Dependovirus (genetics)
  • Female
  • Gliosis (therapy)
  • Humans
  • Immunohistochemistry
  • Male
  • Maze Learning (physiology)
  • Mice
  • Mice, Transgenic
  • Presenilin-1 (genetics)

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