| First Author | Park G | Year | 2020 |
| Journal | Cell Rep | Volume | 31 |
| Issue | 13 | Pages | 107839 |
| PubMed ID | 32610140 | Mgi Jnum | J:301251 |
| Mgi Id | MGI:6489146 | Doi | 10.1016/j.celrep.2020.107839 |
| Citation | Park G, et al. (2020) Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid beta-Protein-Induced Synapse Loss in Alzheimer's Disease. Cell Rep 31(13):107839 |
| abstractText | Amyloid beta-protein (Abeta) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how Abeta causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Abeta-induced synaptic injury is related to the cleavage of amyloid beta precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide. In organotypic slice cultures derived from mice with a knock-in mutation in the APP gene (APP D664A) to inhibit caspase cleavage, Abeta-induced synaptic injury is markedly reduced in two models of Abeta toxicity. Loss of dendritic spines is also attenuated in mice treated with caspase inhibitors. Importantly, the time-dependent dendritic spine loss is correlated with localized activation of caspase-3 but is absent in APP D664A cultures. We propose that the APP cytosolic domain plays an essential role in Abeta-induced synaptic damage in the injury pathway mediated by localized caspase activation. |
