Molecular Effects Of PS1 Deficiency On ER Stress

Presenilin 1 (PS1) has been known as the composition of γ-secretase, participating in the production of A(3. Mutations of PS1 can lead to Aβ accumulation in neurons, which triggers a common type of dementia-Alzheimer’s disease (AD). PS1/PS2 conditional knockout mice show similar symptoms as AD independent of A β accumulation. Analyses of AD patients’ brain tissue and mice expressing mutant forms of APP or PS proteins showed alterations in calcium metabolism happened in the early stages of the pathology. Endoplasmic reticulum (ER) is the major intracellular calcium storage sites. PS1 mainly locates in ER and Golgi and forms calcium leak channel, which is responsible for functional homeostasis of calcium signaling cells. All of these evidence suggest that PS1 is essential for proper functioning of ER. In a previous study, we characterized a mitochondrial apoptotic signaling, i.e., PARL-OPA1 pathway, which is responsible for the neuronal death triggered by loss of PS1 function. In this study we attempted to further reveal the molecular interaction of PS deficiency with the ER stress, which was hypothesed to be also contributed to neuronal apoptosis induced by the loss of function of PS. By using a PS knockdown cell model, we demonstrated that loss of PS1 would cause ER stress and activate UPR responds mainly through PERK and ATF6 pathways. Detection of intracellular calcium concentration displayed that calcium concentration was significantly low in PS1 knockdown group as compared with the control group, suggesting that loss of PS1 could disturb calcium homeostasis and cause ER stress, which might contribute to imbalance between the cellular survival and apoptotic signaling in favor of the apoptosis. The results of TUNEL also revealed that the apoptosis rate of the PS1 knockdown cells was significantly higher compared to the wild-type control. Detection of apoptosis-related proteins in the endoplasmic reticulum further demonstrated that PS1 deficiency-mediated apoptosis might possibly be related to the changes in PERK-ATF4-CHOP pathway. Our results thus provided a possible molecular explaination for the PS loss of function of AD pathology and for further understanding the biological and physiological functions of PS1.