Conformationally distinct aggregates of the Amyloid β (Aβ) peptide accumulate in brains of Alzheimer’s disease (AD) patients, but the roles of the different aggregates in disease progression are not clear. We previously isolated two single-chain variable domain antibody fragments (scFvs), C6T and A4, that selectively bind different toxic conformational variants of oligomeric Aβ. Here we utilize these scFvs to localize the presence of these Aβ variants in human AD brain and to demonstrate their potential as therapeutic agents for treating AD. Both A4 and C6T label oligomeric Aβ in extracellular amyloid plaques, while C6T also labels intracellular oligomeric Aβ in human AD brain tissue and in an AD mouse model. For therapeutic studies, the A4 and C6T scFvs were expressed in the AD mice by viral infection of liver cells. The scFvs were administered at 2 months of age and mice sacrificed at 9 months. The scFvs contained a peptide tag to facilitate transport across the blood brain barrier. While treatment with C6T only slightly decreased Aβ deposits and plaque-associated inflammation, it restored neuronal integrity to wild-type levels, significantly promoted growth of new neurons, and impressively rescued survival rates to wild type levels. Treatment with A4 on the other hand significantly decreased Aβ deposits, but did not significantly decrease neuroinflammation or promote neuronal integrity, neurogenesis or survival rate. These results suggest that the specific Aβ conformation targeted in therapeutic applications greatly affects the outcome, and the location of the targeted Aβ variants may also play a critical factor.
P1-227: Expression of anti-Aβ single-chain antibody in skeletal muscle reduces Aβ accumulation in an Alzheimer's disease mouse model
