| First Author | Park HJ | Year | 2015 |
| Journal | EMBO J | Volume | 34 |
| Issue | 12 | Pages | 1674-86 |
| PubMed ID | 25964433 | Mgi Jnum | J:222939 |
| Mgi Id | MGI:5646062 | Doi | 10.15252/embj.201488795 |
| Citation | Park HJ, et al. (2015) The stress response neuropeptide CRF increases amyloid-beta production by regulating gamma-secretase activity. EMBO J 34(12):1674-86 |
| abstractText | The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-beta (Abeta) production. In cells, CRF treatment increases Abeta production and triggers CRF receptor 1 (CRFR1) and gamma-secretase internalization. Co-immunoprecipitation studies establish that gamma-secretase associates with CRFR1; this is mediated by beta-arrestin binding motifs. Additionally, CRFR1 and gamma-secretase co-localize in lipid raft fractions, with increased gamma-secretase accumulation upon CRF treatment. CRF treatment also increases gamma-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate gamma-secretase activity. Unexpectedly, CRFR1 antagonists also increased Abeta. These data collectively link CRF to increased Abeta through gamma-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Abeta and in some cases preferentially increase Abeta42 via complex effects on gamma-secretase. |
