Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid β, amyloid β40, and amyloid β42 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, Todd E. Golde

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Accumulation of amyloid β protein (Aβ) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting Aβ are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-Aβ single-chain variable fragments (scFvs) as a potentially safer form of anti-Aβ immunotherapy. We have generated and characterized three anti-Aβ scFvs that recognize Aβ1-16, Aβx-40, or Aβx-42. To achieve widespread brain delivery, constructs expressing these anti-Aβ 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-Aβ scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Aβ deposition by 25-50%. These data suggest that intracranial anti-Aβ 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.

Original languageEnglish (US)
Pages (from-to)11923-11928
Number of pages6
JournalJournal of Neuroscience
Volume26
Issue number46
DOIs
StatePublished - Nov 15 2006

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Single-Chain Antibodies
Dependovirus
Amyloid beta-Protein Precursor
Amyloid
Alzheimer Disease
Pathology
Amyloidogenic Proteins
Passive Immunization
Brain
Immunotherapy
Transgenic Mice
Vaccination
Costs and Cost Analysis
Therapeutics

Keywords

  • Adeno-associated virus
  • Alzheimer's disease
  • Amyloid; Aβ
  • Immunotherapy
  • Single-chain variable fragments

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid β, amyloid β40, and amyloid β42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. / Levites, Yona; Jansen, Karen; Smithson, Lisa A.; Dakin, Rachel; Holloway, Vallie M.; Das, Pritam; Golde, Todd E.

In: Journal of Neuroscience, Vol. 26, No. 46, 15.11.2006, p. 11923-11928.

Research output: Contribution to journalArticle

Levites, Yona ; Jansen, Karen ; Smithson, Lisa A. ; Dakin, Rachel ; Holloway, Vallie M. ; Das, Pritam ; Golde, Todd E. / Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid β, amyloid β40, and amyloid β42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 46. pp. 11923-11928.
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