The impact of the unfolded protein response on human neurons carrying the familial Alzheimer's disease PSEN1-deltaE9 mutation
- Author(s): Chen, Andrew G.;
- Advisor(s): Goldstein, Lawrence;
- et al.
Alzheimer’s disease (AD) is characterized by extensive cell death and accumulation of misfolded proteins in the brain, which consist of amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs). We sought to determine the effects of endoplasmic reticulum (ER) stress on classical AD characteristics in neurons and neural stem cells (NSCs). We used isogenic human induced pluripotent stem cell (hiPSC)-derived neurons and NSCs that were genetically modified with the presenilin 1 exon 9 deletion (PS1-ΔE9) mutation. We found that after two days, tunicamycin induced cell death in the PS1-ΔE9 neurons, but not wild type neurons; treatment for five days with thapsigargin, however, induced more cell death in wild type neurons than PS1-∆E9 neurons.
While previous studies have suggested connections between ER stress, Aβ, and phosphorylated tau (P-tau), results have remained controversial. To measure the effects of ER stress on Aβ42/Aβ40 and P-tau/T-tau (total tau) ratios, we treated neurons with tunicamycin or thapsigargin for two or five days. We observed no change in Aβ42/Aβ40 ratio with tunicamycin or thapsigargin, but observed a dose- and time-dependent reduction in overall Aβ42 and Aβ40 levels. P-tau/T-tau ratio was decreased in PS1-∆E9, but not wild type neurons in response to both tunicamycin and thapsigargin at 2 days. However, after 5 days of treatment we observed reduced P-tau/T-tau ratio in response to tunicamycin only in wild type and PS1-∆E9 neurons. The results presented in this study show that the PS1-∆E9 mutation sensitizes and confers resistance to neurons in response to different ER stressors, and suggest that ER stress may rescue AD phenotypes.