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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 , Amyloid 40, and Amyloid 42 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 protein (A) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting A are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-A single-chain variable fragments (scFvs) as a potentially safer form of anti-A immunotherapy. We have generated and characterized three anti-A scFvs that recognize A1–16, Ax-40, or Ax-42. To achieve widespread brain delivery, constructs expressing these anti-A 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-A scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased A deposition by 25–50%. These data suggest that intracranial anti-A 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; A

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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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