The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐secretase activity

• DOI: 10.15252/embj.201488795
• Publication Date: 2015-05-12T01:02:08Z
• Authors: Hyo‐Jin Park; Yong Ran; Joo In Jung; Oliver Holmes; Ashleigh R Price; Lisa Smithson; Carolina Ceballos...; Chul Han; Michael S Wolfe; Yehia Daaka; Andrey E Ryabinin; Seong‐Hun Kim; Richard L Hauger; Todd E Golde; Kevin M Felsenstein
• Keywords: 0301 basic medicine; Aging; Biomedical and clinical sciences; Corticotropin-Releasing Hormone; Pituitary-Adrenal System; Neurodegenerative; Alzheimer's Disease; Inbred C57BL; Medical and Health Sciences; corticotrophin releasing factor; stress; Mice; Models; Receptors; Cyclic AMP; 2.1 Biological and endogenous factors; gamma-secretase; Microscopy; Blotting; Biological Sciences; amyloid-beta; 3. Good health; Biological sciences; 5.1 Pharmaceuticals; Western; Hypothalamo-Hypophyseal System; Physiological; Blotting, Western; 610; Enzyme-Linked Immunosorbent Assay; Stress; Real-Time Polymerase Chain Reaction; Models, Biological; Fluorescence; 03 medical and health sciences; Membrane Microdomains; amyloid‐β; Alzheimer Disease; Information and Computing Sciences; 616; Acquired Cognitive Impairment; Animals; Humans; Immunoprecipitation; γ‐secretase; beta-arrestin; Analysis of Variance; Amyloid beta-Peptides; Neurosciences; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Biological; Brain Disorders; Mice, Inbred C57BL; HEK293 Cells; Microscopy, Fluorescence; Dementia; Biochemistry and Cell Biology; Amyloid Precursor Protein Secretases; β‐arrestin; Developmental Biology

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.