Single chain Fv antibodies against the 25-35 Aβ fragment inhibit aggregation and toxicity of Aβ42

Alzheimer's disease (AD) is characterized by the deposition of amyloid-β (Aβ) protein in the brain. Immunization studies have demonstrated that anti-Aβ antibodies reduce Aβ 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 Aβ 25-35 region as potential therapeutics for AD that do not risk an inflammatory response. The 25-35 region of Aβ represents a promising therapeutic target since it promotes aggregation and is highly toxic. Two scFvs with differing affinities for Aβ were studied, and both inhibited aggregation of Aβ42 as determined by thioflavin T binding assay and atomic force microscopy analysis and blocked Aβ-induced toxicity toward human neuroblastoma SH-SY5Y cells as determined by MTT and LDH release assays. These results provide additional evidence that scFvs against Aβ provide an attractive alternative to more conventional antibody-based therapeutics for controlling aggregation and toxicity of Aβ.