Evidence against a contribution of the CCAAT-enhancer binding protein homologous protein (CHOP) in mediating neurotoxicity in rTg4510 mice

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.

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD

“…Our data show that knockdown of Chop using ASO decreased Chop expression, but had no impact on motor deficits or overall TDP-43 pathology. These findings are consistent with previous reports that neither genetic knockout nor ASOmediated knockdown of Chop led to beneficial outcomes in the mutant SOD1 G93A mouse model of ALS [20,51] or rTg4510 mice for Alzheimer's disease [52]. Nevertheless, we did detect a slight albeit statistically significant decrease of insoluble TDP-43 CTFs in ASO-treated rNLS8 mice.…”

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS/FTD

“…Our data show that knockdown of Chop using ASO decreased Chop expression (Supplementary Fig 2), but had no impact on overall TDP-43 pathology (Fig 5) or motor deficits (Fig 4). These findings are consistent with previous reports that neither genetic knockout nor ASO-mediated knockdown of Chop led to beneficial outcomes in the mutant SOD1 G93A mouse model for ALS (18, 36) or rTg4510 mice for Alzheimer’s disease (37).…”

“…Our data show that knockdown of Chop using ASO decreased Chop expression (Supplementary Fig 2 ), but had no impact on overall TDP-43 pathology (Fig 5) or motor deficits (Fig 4). These findings are consistent with previous reports that neither genetic knockout nor ASO-mediated knockdown of Chop led to beneficial outcomes in the mutant SOD1 G93A mouse model for ALS (18,36) or rTg4510 mice for Alzheimer's disease (37). Prolonged ISR activation induces apoptosis via cell death downstream of the intrinsic pathway that is regulated by Bcl2 family members (Bim, Noxa, Puma), and the extrinsic pathway (Bid) that can be triggered by various cell death signals (10).…”