| First Author | Deyts C | Year | 2016 |
| Journal | Elife | Volume | 5 |
| PubMed ID | 27196744 | Mgi Jnum | J:234011 |
| Mgi Id | MGI:5788788 | Doi | 10.7554/eLife.15645 |
| Citation | Deyts C, et al. (2016) Loss of presenilin function is associated with a selective gain of APP function. Elife 5:e15645 |
| abstractText | Presenilin 1 (PS1) is an essential gamma-secretase component, the enzyme responsible for amyloid precursor protein (APP) intramembraneous cleavage. Mutations in PS1 lead to dominant-inheritance of early-onset familial Alzheimer's disease (FAD). Although expression of FAD-linked PS1 mutations enhances toxic Abeta production, the importance of other APP metabolites and gamma-secretase substrates in the etiology of the disease has not been confirmed. We report that neurons expressing FAD-linked PS1 variants or functionally deficient PS1 exhibit enhanced axodendritic outgrowth due to increased levels of APP intracellular C-terminal fragment (APP-CTF). APP expression is required for exuberant neurite outgrowth and hippocampal axonal sprouting observed in knock-in mice expressing FAD-linked PS1 mutation. APP-CTF accumulation initiates CREB signaling cascade through an association of APP-CTF with Galphas protein. We demonstrate that pathological PS1 loss-of-function impinges on neurite formation through a selective APP gain-of-function that could impact on axodendritic connectivity and contribute to aberrant axonal sprouting observed in AD patients. |
