Relationship between function of presenilin 1 and abnormal phosphorylation of tau

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Missense mutations in the presenilin 1 (PS1) gene on chromosome 14 are known to cause early-onset familial Alzheimer's disease. However the function of PS1 is still unclear. Because PS1 resides in the endoplasmic reticulum (ER), it is very interesting how PS1 affects ER stress response. Our previous report showed that PS1 is induced at Gerbil hippocampus after transient ischemia and that these induction is prominent at the area reported to be resistant to ischemia. Here we study whether mutant PS1 alters the function to ER stress compared with wild PS1. Either A246E or wild PS1 was tranfected to 293T cells with lipofectoamine and cultured for 3 days. The cells were tormented by adding either Ca ionophore (A23187 ; 0.01-5μM) or tunicamycin (0.01-10μg/ml) as ER stress. Twelve hours later, the induction of GRP78 was detected by Northern blotting. The induction of GRP 78 in cell with mutant PS1 was inhibited compared with wild type. The induction of GRP 78 is reported as one of unfolded protein response that functions when unfolded proteins are accumulated in ER under stress conditions. These results suggest that mutation of PS1 may cause the vulnerability to stress related with the pathogenesis of Alzheimer's disease.