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

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. Synopsis Excessive activation of the hypothalamic–pituitary–adrenal (HPA) stress axis may be a risk factor for Alzheimer's disease. Stress exacerbates amyloid‐β (Aβ) accumulation in various animal models. Here we show that: Corticotropin releasing factor (CRF), a critical stress response mediator, increases Aβ production in cells and non‐transgenic mice. γ‐secretase interacts with CRF receptor 1 (CRFR1) through β‐arrestins. Upon CRF binding to CRFR1, γ‐secretase–CRFR1 complex moves into lipid rafts and endosomes where γ‐secretase activity increases. CRF and CRFR antagonists activate γ‐secretase in vitro through CRFR1‐independent mechanisms. Graphical Abstract The critical stress mediator corticotropin releasing factor (CRF) increases amyloid‐β production by altering γ‐secretase localization and activity, thus providing a link between stress and amyloid‐β pathology.