title: Generating differentially targeted amyloid-beta specific intrabodies as a passive vaccination strategy for Alzheimer's disease.
abstract: 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.
authors.affiliation: Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Sudol
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mastrangelo
authors.forename: Wade C
authors.initials: WC
authors.lastname: Narrow
authors.forename: Maria E
authors.initials: ME
authors.lastname: Frazer
authors.forename: Yona R
authors.initials: YR
authors.lastname: Levites
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
authors.forename: William J
authors.initials: WJ
authors.lastname: Bowers
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D004721:Endoplasmic Reticulum; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D014611:Vaccination; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D007135:Immunoglobulin Variable Region; D016875:tau Proteins; D004318:Doxycycline