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: 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
• Journal: The EMBO journal (EMBO J) Vol. 34 Issue 12 Pg. 1674-86 (Jun 12 2015) ISSN: 1460-2075 [Electronic] England
• PMID: 25964433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 The Authors.

Chemical References

• Amyloid beta-Peptides
• Receptors, Corticotropin-Releasing Hormone
• Corticotropin-Releasing Hormone
• Cyclic AMP
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (etiology, metabolism)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (biosynthesis)
• Analysis of Variance
• Animals
• Blotting, Western
• Corticotropin-Releasing Hormone (metabolism)
• Cyclic AMP (metabolism)
• Enzyme-Linked Immunosorbent Assay
• HEK293 Cells
• Humans
• Hypothalamo-Hypophyseal System (physiology)
• Immunoprecipitation
• Membrane Microdomains (metabolism)
• Mice
• Mice, Inbred C57BL
• Microscopy, Fluorescence
• Models, Biological
• Pituitary-Adrenal System (physiology)
• Real-Time Polymerase Chain Reaction
• Receptors, Corticotropin-Releasing Hormone (metabolism)
• Stress, Physiological (physiology)