| First Author | Sapkota D | Year | 2022 |
| Journal | Brain | Volume | 145 |
| Issue | 9 | Pages | 2982-2990 |
| PubMed ID | 36001414 | Mgi Jnum | J:351557 |
| Mgi Id | MGI:7702383 | Doi | 10.1093/brain/awac199 |
| Citation | Sapkota D, et al. (2022) Aqp4 stop codon readthrough facilitates amyloid-beta clearance from the brain. Brain 145(9):2982-2990 |
| abstractText | Alzheimer's disease is initiated by the toxic aggregation of amyloid-beta. Immunotherapeutics aimed at reducing amyloid beta are in clinical trials but with very limited success to date. Identification of orthogonal approaches for clearing amyloid beta may complement these approaches for treating Alzheimer's disease. In the brain, the astrocytic water channel Aquaporin 4 is involved in clearance of amyloid beta, and the fraction of Aquaporin 4 found perivascularly is decreased in Alzheimer's disease. Further, an unusual stop codon readthrough event generates a conserved C-terminally elongated variant of Aquaporin 4 (AQP4X), which is exclusively perivascular. However, it is unclear whether the AQP4X variant specifically mediates amyloid beta clearance. Here, using Aquaporin 4 readthrough-specific knockout mice that still express normal Aquaporin 4, we determine that this isoform indeed mediates amyloid beta clearance. Further, with high-throughput screening and counterscreening, we identify small molecule compounds that enhance readthrough of the Aquaporin 4 sequence and validate a subset on endogenous astrocyte Aquaporin 4. Finally, we demonstrate these compounds enhance brain amyloid-beta clearance in vivo, which depends on AQP4X. This suggests derivatives of these compounds may provide a viable pharmaceutical approach to enhance clearance of amyloid beta and potentially other aggregating proteins in neurodegenerative disease. |
