title: The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity.
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.
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA Department of Pharmacology and Therapeutics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ran
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Joo In
authors.initials: JI
authors.lastname: Jung
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Holmes
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Ashleigh R
authors.initials: AR
authors.lastname: Price
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Smithson
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ceballos-Diaz
authors.affiliation: Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Chul
authors.initials: C
authors.lastname: Han
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolfe
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Yehia
authors.initials: Y
authors.lastname: Daaka
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Ryabinin
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Seong-Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Center of Excellence for Stress and Mental Health, Department of Psychiatry, VA Healthcare System, University of California, San Diego, CA, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hauger
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA tgolde@ufl.edu kfelsenstein0@ufl.edu.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA tgolde@ufl.edu kfelsenstein0@ufl.edu.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Felsenstein
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D047468:Immunoprecipitation; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010913:Pituitary-Adrenal System / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D053829:Amyloid Precursor Protein Secretases
keywords: amyloid‐β; corticotrophin releasing factor; stress; β‐arrestin; γ‐secretase