Alzheimers Dement. 2021 Dec;17 Suppl 2
e058717
BACKGROUND: In Alzheimer's disease (AD), the accumulation of the microtubule associated protein tau is linked with neuronal loss, but the major cell death pathway remains to be identified. Pathogenic tau promotes endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR) activation. However, the contribution of ER stress to tau-mediated toxicity in neurons is unknown. A previous study demonstrated that mice lacking CHOP/Ddit3, an important regulator of ER stress-induced cell death, were protected from ER stress induced neuronal loss. We hypothesized that silencing CHOP would prevent tau toxicity through the ER stress pathway and reveal the contribution of tau toxicity that is mediated through this pathway.METHOD: To investigate this, we generated a mouse-targeting CHOP/Ddit3 shRNA AAV9 that also expresses GFP by a separate promoter. We injected shCHOP AAV9 or a shScrambled control AAV9 in the brains of 8-month-old male and female rTg4510 tau transgenic mice and harvested them at 12-months of age, when ER stress is activated, and neuronal loss is occurring in these mice. We performed behavioral studies using the Y-Maze, Open field, and 2-day Radial-Arm water maze task with a reversal paradigm. Unbiased stereology was used to determine neuronal health and effect of CHOP shRNA on CHOP levels was evaluated by immunofluorescence.
RESULT: AAV9 CHOP shRNA did not alter spatial learning and memory in tau transgenic mice. Evaluation of the tissue revealed a modest, but non-significant increase in neuronal loss from CHOP knock down, while the DG shows a non-significant decrease in neuronal loss. Tissue volume was unchanged in both regions. Very surprising to us, and opposite of what was expected, we found that in these regions of interest the CHOP levels increased in the animal expressing the CHOP.
CONCLUSION: Overall, this suggests that shCHOP AAV9 does not alter tau-modified behaviors such as learning and memory particularly at this timepoint. Our results also suggest that there may be a compensatory increase in CHOP signaling in neighboring cells, suggesting that the activation of the UPR in the brains of these mice may be a protective mechanism.