| First Author | Wang H | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 52 | Pages | E12427-E12434 |
| PubMed ID | 30530690 | Mgi Jnum | J:269161 |
| Mgi Id | MGI:6272055 | Doi | 10.1073/pnas.1815915115 |
| Citation | Wang H, et al. (2018) Spatiotemporal activation of the C/EBPbeta/delta-secretase axis regulates the pathogenesis of Alzheimer's disease. Proc Natl Acad Sci U S A 115(52):E12427-E12434 |
| abstractText | Alzheimer's disease (AD) neuropathological hallmarks include senile plaques with aggregated amyloid beta as a major component, neurofibrillary tangles (NFT) containing truncated and hyperphosphorylated Tau, extensive neuronal loss, and chronic neuroinflammation. However, the key molecular mechanism that dominates the pathogenesis of AD remains elusive for AD. Here we show that the C/EBPbeta/delta-secretase axis is activated in an age-dependent manner in different brain regions of the 3xTg AD mouse model, elevating delta-secretase-truncated APP and Tau proteolytic truncates and promoting senile plaques and NFT formation in the brain, associated with gradual neuronal loss and chronic neuroinflammation. Depletion of inflammatory cytokine-regulated transcription factor C/EBPbeta from 3xTg mice represses APP, Tau, and delta-secretase expression, which subsequently inhibits APP and Tau cleavage, leading to mitigation of AD pathologies. Knockout of delta-secretase from 3xTg mice strongly blunts AD pathogenesis. Consequently, inactivation of the C/EBPbeta/delta-secretase axis ameliorates cognitive dysfunctions in 3xTg mice by blocking APP and Tau expression and their pathological fragmentation. Thus, our findings support the notion that C/EBPbeta/delta-secretase axis plays a crucial role in AD pathogenesis. |
