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The Journal of Neuroscience, November 15, 2006, 26(46):11923-11928; doi:10.1523/JNEUROSCI.2795-06.2006

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Neurobiology of Disease
Intracranial Adeno-Associated Virus-Mediated Delivery of Anti-Pan Amyloid beta, Amyloid beta40, and Amyloid beta42 Single-Chain Variable Fragments Attenuates Plaque Pathology in Amyloid Precursor Protein Mice

Yona Levites, Karen Jansen, Lisa A. Smithson, Rachel Dakin, Vallie M. Holloway, Pritam Das, and Todd E. Golde

Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, Florida 32224

Correspondence should be addressed to Todd E. Golde, Department of Neuroscience, Mayo Clinic Jacksonville, Birdsall 210, 4500 San Pablo Road, Jacksonville, FL 32224. Email: tgolde{at}mayo.edu

Accumulation of amyloid beta protein (Abeta) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting Abeta are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-Abeta single-chain variable fragments (scFvs) as a potentially safer form of anti-Abeta immunotherapy. We have generated and characterized three anti-Abeta scFvs that recognize Abeta1–16, Abetax-40, or Abetax-42. To achieve widespread brain delivery, constructs expressing these anti-Abeta scFvs were packaged into adeno-associated virus (AAV) vectors and injected into the ventricles of postnatal day 0 (P0) amyloid precursor protein CRND8-transgenic mice. Intracranial delivery of AAV to neonatal mice resulted in widespread neuronal delivery. In situ expression of each of the anti-Abeta scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Abeta deposition by 25–50%. These data suggest that intracranial anti-Abeta scFv expression is an effective strategy to attenuate amyloid deposition. As opposed to transgenic approaches, these studies also establish a "somatic brain transgenic" paradigm to rapidly and cost-effectively evaluate potential modifiers of AD-like pathology in AD mouse models.

Key words: single-chain variable fragments; immunotherapy; Alzheimer's disease; adeno-associated virus; amyloid; Abeta


Received June 30, 2006; revised Sept. 26, 2006; accepted Oct. 6, 2006.

Correspondence should be addressed to Todd E. Golde, Department of Neuroscience, Mayo Clinic Jacksonville, Birdsall 210, 4500 San Pablo Road, Jacksonville, FL 32224. Email: tgolde{at}mayo.edu




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