Abstract

Tau accumulation and progressive loss of neurons are associated with Alzheimer’s disease (AD). Aggregation of tau has been associated with endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR). While ER stress and the UPR have been linked to AD, the contribution of these pathways to tau-mediated neuronal death is still unknown. We tested the hypothesis that reducing C/EBP Homologous Protein (CHOP), a UPR induced transcription factor associated with cell death, would mitigate tau-mediated neurotoxicity through the ER stress pathway. To evaluate this, 8.5-month-old male rTg4510 tau transgenic mice were injected with a CHOP-targeting or scramble shRNA AAV9 that also expressed EGFP. Following behavioral assessment, brain tissue was collected at 12 months, when ER stress and neuronal loss is ongoing. No behavioral differences in locomotion, anxiety-like behavior, or learning and memory were found in shCHOP mice. Unexpectedly, mice expressing shCHOP had higher levels of CHOP, which did not affect neuronal count, UPR effector (ATF4), or tau tangles. Overall, this suggests that CHOP is a not a main contributor to neuronal death in rTg4510 mice. Taken together with previous studies, we conclude that ER stress, including CHOP upregulation, does not worsen outcomes in the tauopathic brain.

Details

Title
Evidence against a contribution of the CCAAT-enhancer binding protein homologous protein (CHOP) in mediating neurotoxicity in rTg4510 mice
Author
Criado-Marrero, Marangelie 1 ; Blazier, Danielle M. 1 ; Gould, Lauren A. 1 ; Gebru, Niat T. 1 ; Rodriguez Ospina, Santiago 1 ; Armendariz, Debra S. 1 ; Darling, April L. 1 ; Beaulieu-Abdelahad, David 1 ; Blair, Laura J. 2 

 University of South Florida, Department of Molecular Medicine, Morsani College of Medicine, USF Health Byrd Alzheimer’s Institute, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
 University of South Florida, Department of Molecular Medicine, Morsani College of Medicine, USF Health Byrd Alzheimer’s Institute, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X); James A Haley Veterans Hospital, Research Service, Tampa, USA (GRID:grid.281075.9) (ISNI:0000 0001 0624 9286) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2659830517
Copyright
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.