| First Author | He P | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100241 | PubMed ID | 33376140 |
| Mgi Jnum | J:358898 | Mgi Id | MGI:7783807 |
| Doi | 10.1074/jbc.RA120.015327 | Citation | He P, et al. (2021) A conformation-specific antibody against oligomeric beta-amyloid restores neuronal integrity in a mouse model of Alzheimer's disease. J Biol Chem 296:100241 |
| abstractText | Conformationally distinct aggregates of the amyloid beta (Abeta) peptide accumulate in brains of patients with Alzheimer's disease (AD), 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 Abeta. Here, we utilize these scFvs to localize the presence of these Abeta variants in human AD brain and to demonstrate their potential as therapeutic agents for treating AD. Both A4 and C6T label oligomeric Abeta in extracellular amyloid plaques, whereas C6T also labels intracellular oligomeric Abeta 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 Abeta deposits and plaque-associated inflammation, it restored neuronal integrity to WT levels, significantly promoted growth of new neurons, and impressively rescued survival rates to WT levels. Treatment with A4 on the other hand significantly decreased Abeta deposits but did not significantly decrease neuroinflammation or promote neuronal integrity, neurogenesis, or survival rate. These results suggest that the specific Abeta conformation targeted in therapeutic applications greatly affects the outcome, and the location of the targeted Abeta variants may also play a critical factor. |
