The interplay of aryl hydrocarbon receptor/WNT/CTNNB1/Notch signaling pathways regulate amyloid beta precursor mRNA/protein expression and effected the learning and memory of mice

Majid Keshavarzi; Fatemeh Moradbeygi; Keivan Mobini; Ali Ghaffarian Bahraman; Parisa Mohammadi; Afsaneh Ghaedi; Afshin Mohammadi-Bardbori

doi:10.1093/toxres/tfab120

The interplay of aryl hydrocarbon receptor/WNT/CTNNB1/Notch signaling pathways regulate amyloid beta precursor mRNA/protein expression and effected the learning and memory of mice

Toxicol Res (Camb). 2021 Dec 29;11(1):147-161. doi: 10.1093/toxres/tfab120. eCollection 2022 Feb.

Authors

Majid Keshavarzi¹, Fatemeh Moradbeygi¹, Keivan Mobini¹, Ali Ghaffarian Bahraman¹, Parisa Mohammadi², Afsaneh Ghaedi¹, Afshin Mohammadi-Bardbori¹

Affiliations

¹ Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 7146864685, Iran.
² Department of Environmental Health, Faculty of Health, Sabzevar University of Medical Sciences, Sabzevar 7146864685, Iran.

Abstract

The amyloid beta precursor protein (APP) plays a pathophysiological role in the development of Alzheimer's disease as well as a physiological role in neuronal growth and synaptogenesis. The aryl hydrocarbon receptor (AhR)/WNT/Catenin Beta 1 (CTNNB1)/Notch signaling pathways stamp in many functions, including development and growth of neurons. However, the regulatory role of AhR-/WNT-/CTNNB1-/Notch-induced APP expression and its influence on hippocampal-dependent learning and memory deficits is not clear. Male BALB/C mice received 6-formylindolo[3,2-b]carbazole (an AhR agonist), CH223191(an AhR antagonist), DAPT (an inhibitor of Notch signaling), and XAV-939 (a WNT pathway inhibitor) at a single dose of 100 μg/kg, 1, 5 , and 5 mg/kg of body weight, respectively, via intraperitoneal injection alone or in combination. Gene expression analyses and protein assay were performed on the 7th and 29th days. To assess the hippocampal-dependent memory, all six mice also underwent contextual fear conditioning on the 28th day after treatments. Our results showed that endogenous ligand of AhR has a regulatory effect on APP gene. Also, the interaction of AhR/WNT/CTNNB1 has a positive regulatory effect, but Notch has a negative regulatory effect on the mRNA and protein expression of APP, which have a correlation with mice's learning skills and memory.

Keywords: 2-b]carbazole (FICZ); 6-formylindolo[3; Notch; WNT/CTNNB1; amyloid beta precursor protein (APP); aryl hydrocarbon receptor (AhR); learning and memory.