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

Tomomi 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

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Accumulation of aggregated amyloid-β (Aβ) 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, β-amyloidosis, including suppression of both fibrillar and oligomer Aβ 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.

Original languageEnglish (US)
Pages (from-to)803-809
Number of pages7
JournalMolecular Therapy
Volume17
Issue number5
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Kiyota, T., Yamamoto, M., Schroder, B., Jacobsen, M. T., Swan, R. J., Lambert, M. P., Klein, W. L., Gendelman, H. E., Ransohoff, R. M., & Ikezu, T. (2009). AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, β-amyloidosis, and learning impairment of APP/ PS1 mice. Molecular Therapy, 17(5), 803-809. https://doi.org/10.1038/mt.2009.44