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-b (Ab) production. In cells, CRF treatment increases Ab production and triggers CRF receptor 1 (CRFR1) and c-secretase internalization. Co-immunoprecipitation studies establish that c-secretase associates with CRFR1; this is mediated by b-arrestin binding motifs. Additionally, CRFR1 and c-secretase co-localize in lipid raft fractions, with increased c-secretase accumulation upon CRF treatment. CRF treatment also increases c-secretase activity in vitro, revealing a second, receptorindependent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate c-secretase activity. Unexpectedly, CRFR1 antagonists also increased Ab. These data collectively link CRF to increased Ab through c-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 Ab and in some cases preferentially increase Ab42 via complex effects on c-secretase.

Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

“…CRH interacts with its receptor, the CRHR1 protein; the CRHR1 gene is highly expressed in hippocampus and the complex between the hormone and its receptor (CRH+CRHR1) can be detected in that brain region [37]. In addition, the CRHR1 protein also interacts with γ-secretase, which is associated with Aβ accumulation, one of the hallmarks of AD pathophysiology [38]. Experimental evidences for CRH gene and its receptors CRHR1 and CRHR2 and CRHR1 antagonist 'Antalarmin', collected from mouse model knock-out experiments to identify their role in the stress induced mice Hippocampus: Repeated stress induces the expression of the wild-type CRH gene, while inactivation of the CRHR1 gene, which is the receptor of CRH, not only inhibits the complex of CRH+CRHR1 but also causes a reduction of MAPT phosphorylation and a reduction of Amyloid beta (Aβ) peptide concentration.…”

“…Repetitively, in a recent publication, Park HJ stated that stress response meditated by CRH-CRHR1 mechanism could also contribute to AD pathogenesis [38]. But he also described that under some circumstances, CRHR1 antagonism does not achieve required results against acute stress-induced Aβ production, rather he suggested that either direct targeting of CRH or G protein-biased CRHR1 agonist that could suppress β-arrestin recruitment to CRHR1 might be required to effectively target associated pathway for therapeutic benefit in AD [38].…”

Targeting psychologic stress signaling pathways in Alzheimer’s disease

“…Evaluation of the G s coupled pathway of CRHR1 has shown that pretreatment with the Protein Kinase A (PKA) inhibitor H-89 was able to significantly reduce Aβ40 and Aβ42 production in a CRH treated PNC model [43]. Through these investigations, a picture begins to form that includes three possible mechanisms for CRH induced Aβ increases. CRHR1 interactions with β-arrestin 2 and γ-secretase: demonstrated by the data that CRHR1 antagonists do not stimulate the receptor, but do induce its internalization and increase Aβ40 and Aβ42 production in vitro [44]. …”

“…Dong (2014) - Able to decrease Aβ levels and plaque load in a chronic stress paradigm [43]. Park (2015) - Unable to block rises in Aβ in response to acute stress [44]. Dong (2014) measured PBS soluble Aβ, which represents roughly 5% of total Aβ.A-helical CRHPark et al (2015) [44]5 & 10 μMUnable to block CRH induced Aβ increases in vitro.AstressinPark et al (2015) [44]5 & 10 μMUnable to block CRH induced Aβ increases in vitro.NBI 30775/R121919Rissman et al (2012) [59], Campbell et al (2015) [51], Dong et al (2014) [43], Zhang et al (2016) [64]20 mg/kg.…”

“…Zhang (2016) utilized osmotic mini pumpCampbell (2015) [51] – able to decrease AT8 and PHF-1 phosphorylation in CRH overexpressing mice but not at S262 and S422. Rissman (2012) [59] – Able to decrease stress induced AT8 and PHF-1 increases in phosphorylationNBI27914Park et al (2015) [44], Lee et al (2009) [83], Carroll et al (2011) [54]10 mg/kgCarroll (2011) [54] - NBI27914 rescued freezing and decreased AT8 phosphorylation and decreased neurodegeneration in PS1 tau transgenic mice.Lee (2009) [83] – NBI27914 reduced stress induced increases in Aβ levels and plaque load.Park (2015) [44] – NBI27914 increased secreted Aβ42/ Aβ40 ratio in vitro …”