Single chain Fv antibodies against the 25-35 Abeta fragment inhibit aggregation and toxicity of Abeta42.
Alzheimer's disease (AD) is characterized by the deposition of amyloid-beta (Abeta) protein in the brain. Immunization studies have demonstrated that anti-Abeta antibodies reduce Abeta deposition and improve clinical symptoms seen in AD. However, conventional antibody-based therapies risk an inflammatory response that can result in meningoencephalitis and cerebral hemorrhage. Here we report on the development of human-based single chain variable domain antibody fragments (scFvs) directed against the Abeta 25-35 region as potential therapeutics for AD that do not risk an inflammatory response. The 25-35 region of Abeta represents a promising therapeutic target since it promotes aggregation and is highly toxic. Two scFvs with differing affinities for Abeta were studied, and both inhibited aggregation of Abeta42 as determined by thioflavin T binding assay and atomic force microscopy analysis and blocked Abeta-induced toxicity toward human neuroblastoma SH-SY5Y cells as determined by MTT and LDH release assays. These results provide additional evidence that scFvs against Abeta provide an attractive alternative to more conventional antibody-based therapeutics for controlling aggregation and toxicity of Abeta.
Zameer
Andleeb
A
Department of Chemical and Materials Engineering, Arizona State University, Tempe, Arizona 85287-6006, USA.
Schulz
Philip
P
Wang
Min S
MS
Sierks
Michael R
MR
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology* / Q000633:toxicity* / Q000648:ultrastructure; D000906:Antibodies / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D007700:Kinetics; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000633:toxicity* / Q000648:ultrastructure; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment
D016229:Amyloid beta-Peptides; D000906:Antibodies; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)