Generating differentially targeted amyloid-beta specific intrabodies as a passive vaccination strategy for Alzheimer's disease
| Autor: | Maria E Frazer, Todd E. Golde, Kelly L. Sudol, Wade C. Narrow, Yona Levites, Howard J. Federoff, William J. Bowers, Michael A. Mastrangelo |
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| Rok vydání: | 2009 |
| Předmět: |
Transgene
Genetic Vectors Immunoglobulin Variable Region Mice Transgenic tau Proteins Endoplasmic Reticulum Intrabody Epitope Antibodies 03 medical and health sciences Amyloid beta-Protein Precursor Mice 0302 clinical medicine Alzheimer Disease Drug Discovery Genetics medicine Amyloid precursor protein Animals Humans Molecular Biology Cells Cultured 030304 developmental biology Pharmacology 0303 health sciences biology Endoplasmic reticulum Vaccination Original Articles Dependovirus medicine.disease Molecular biology 3. Good health Cell biology Disease Models Animal Doxycycline biology.protein Molecular Medicine Antibody Alzheimer's disease 030217 neurology & neurosurgery Intracellular |
| Zdroj: | Molecular therapy : the journal of the American Society of Gene Therapy. 17(12) |
| ISSN: | 1525-0024 |
| Popis: | Amyloid-beta (A beta) has been identified as a key component in Alzheimer's disease (AD). Significant in vitro and human pathological data suggest that intraneuronal accumulation of A beta peptides plays an early role in the neurodegenerative cascade. We hypothesized that targeting an antibody-based therapeutic to specifically abrogate intracellular A beta accumulation could prevent or slow disease onset. A beta 42-specific intracellular antibodies (intrabodies) with and without an intracellular trafficking signal were engineered from a previously characterized single-chain variable fragment (scFv) antibody. The intrabodies, one with an endoplasmic reticulum (ER) targeting signal and one devoid of a targeting sequence, were assessed in cells harboring a doxycycline (Dox)-regulated mutant human amyloid precursor protein Swedish mutant (hAPP(swe)) transcription unit for their abilities to prevent A beta peptide egress. Adeno-associated virus (AAV) vectors expressing the engineered intrabodies were administered to young adult 3xTg-AD mice, a model that develops amyloid and Tau pathologies, prior to the initial appearance of intraneuronal A beta. Chronic expression of the ER-targeted intrabody (IB) led to partial clearance of A beta 42 deposits and interestingly, in reduced staining for a pathologic phospho-Tau epitope (Thr231). This approach may provide insights into the functional relevance of intraneuronal A beta accumulation in early AD and potentially lead to the development of new therapeutics. |
| Databáze: | OpenAIRE |
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