The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐secretase activity |
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| Authors: | Hyo‐Jin Park Yong Ran Joo In Jung Oliver Holmes Ashleigh R Price Lisa Smithson Carolina Ceballos‐Diaz Chul Han Michael S Wolfe Yehia Daaka Andrey E Ryabinin Seong‐Hun Kim Richard L Hauger Todd E Golde Kevin M Felsenstein |
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| Affiliation: | 1. Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA;2. Department of Pharmacology and Therapeutics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, USA;3. Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA;4. Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, FL, USA;5. Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA;6. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA;7. Center of Excellence for Stress and Mental Health, Department of Psychiatry, VA Healthcare System, University of California, San Diego, CA, USA |
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| Abstract: | 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‐β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ‐secretase internalization. Co‐immunoprecipitation studies establish that γ‐secretase associates with CRFR1; this is mediated by β‐arrestin binding motifs. Additionally, CRFR1 and γ‐secretase co‐localize in lipid raft fractions, with increased γ‐secretase accumulation upon CRF treatment. CRF treatment also increases γ‐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 γ‐secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ‐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 Aβ and in some cases preferentially increase Aβ42 via complex effects on γ‐secretase. |
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| Keywords: | β ‐arrestin γ ‐secretase amyloid‐β corticotrophin releasing factor stress |
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