The Influence Of PS1 Loss Of Function On The Interaction Of Mitochondrial Apoptotic Pathway And ER Stress

Alzheimer’s disease (Alzheimer diseases, AD) is the commonest form of neurodegenerative diseases characterized clinically by cognitive disabilities and pathologically by excessive deposition of A(3 and formation of intraneuronal neurofibrillary tangles. Recent studies have shown that neuronal apoptosis is closely associated with abnormal functions of mitochondria and endoplasmic reticulum. We previously found that both mitochondrial structure and function appeared to be abnormal in PS 1/2 cDKO mice and that PS deficiency-induced neuronal apoptosis could be modulated by mitochondrial PS1-PARL-OPA1 signaling pathway, in which overexpression of PARL could counteract OPA1 reduction and the apoptotic process, in the PS 1-knockdown SH-SY5Y cells. In the present study, we augmented evidence that the expressions of PARL and OPA1 were decreased at both RNA and protein levels in the brain of PS 1/2 cDKO mice, in line with that observed in PS1-knockdown SH-SY5Y cells. Furthermore, the results from the experiments in PS1-knockdown SH-SY5Y cells showed that overexpression of OPA1, a downstream component of PARL, did not result in amelioration of PS 1-knockdown induced apoptosis, suggesting that OPA1 could be unable to function properly when PARL was impaired by the loss-of-function of PS1.Mitochondria and endoplasmic reticulum (ER) are two different cellular constituents with not only their own specific roles, but intimated interaction as well, in governing cellular homeostasis and biochemical/physiological functions. In addition to having structural and functional effects on mitochondria, PS1 has also been reported to be involved in ER function by forming ER calcium leak channel. Our previous study also found that PS1 loss-of function caused ER stress in PS 1-knockdown SH-SY5Y cells. How do the mitochondria and ER interact under the condition of PS1 deficiency and what are the consequences of their interaction in determining cell fate, however, remain unclear. Results of the present study revealed that PS 1-knockdown resulted e ER stress, presumably being weak in strength, had no obvious effect on PS1 deficiency-activated mitochondrial PARL-OPA1 apoptotic signaling pathway. When the ER stress was further augmented to a mild extent by using an ER stress inducer, tunicamycin, in the PS1 knockdown SH-SY5Y cells, however, the PARL expression and the cytochrome C levels in mitochondria were elevated that counteracted the PSl-knockdown-broughted reductions of this gene/protein and cytochrome C. Notably, the up-regulating effect of tunicamycin-induced mild ER stress on PARL expression was only observable in PS1 deficiency, but not WT SH-SY5Y cells. Thus, our data suggest that tunicamycin-induced ER stress could prevent PS1 deficiency neuronal cells from apoptosis via up-regulation of PARL and hereby inhibiting the activation of mitochondrial PS1-PARL-OPA1 apoptosis pathway, and that such a protective role of ER stress might be dependent not only on the stress extent, but also on PS1 loss-of function. Proper modulation of the interaction between mitochondria and ER stress might be considered to be a possible approach towards inhibition of PS1 deficiency-induced neuronal apoptosis. Further study, especially in vivo in PS 1/2 cDKO mice, to validate the cellular findings is necessary.