Abstract
Conformationally distinct aggregates of the amyloid β (Aβ) 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 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, whereas 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 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 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.
Highlights
Distinct aggregates of the amyloid β (Aβ) peptide accumulate in brains of patients with Alzheimer’s disease (AD), but the roles of the different aggregates in disease progression are not clear
The hypothesis that oligomeric Aβ species are responsible for AD pathogenesis rather than the fibrillar amyloid plaques is supported by many studies including a mouse model engineered to express oligomeric Aβ but not plaques [6, 9], This article contains supporting information. * For correspondence: Michael R
We showed that the A4- and C6Trecognized oligomeric Aβ variants could both be detected in human brain tissue [18], cerebral spinal fluid [25], as well as sera samples [25, 26]
Summary
We previously isolated two scFv fragments, A4 and C6T, against two conformationally distinct oligomeric Aβ species, one synthetically generated, and one human AD brain derived (Table 1) [17, 18, 21]. We did not find any expression of the oligomeric Aβ variants recognized by C6T and A4 in the brains of WT mice (Fig. 2, A and B), similar to our observations with ND human brain tissue (Fig. 1, A and B). A significant decrease in the number of Congo red deposits was observed in both the cortex (Fig. 3E; *p < 0.05) and hippocampus (Fig. 3F; *p < 0.05) in brain tissue of mice treated with rAAV-A4 and rAAV-C6T compared with littermate GFP vehicle-treated mice. Similar to the results obtained with the 6E10-labeled plaques (Fig. 3B), a significant decrease in the number of Congo red structures was observed in the cortex in mice treated with rAAV-A4 compared with rAAV-C6T (Fig. 3F; &p < 0.05), and levels were lower in the hippocampus. Mice treated with rAAV-A4 showed reduced plaque formation compared with mice treated with rAAVC6T, whereas mice treated with rAAV-C6T showed significantly reduced reactive microglia compared with the rAAVA4 group (Fig. 4B; &p < 0.05)
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