We report a PS1 gene mutation (Val 97Leu) in a Chinese familial Alzheimer's disease (FAD) pedigree and a cell model of FAD built by transfecting PS1 v97L mutants into human neuroblastoma SH-SY5Y cells. To test our hypothesis that the PS1 v97L mutation is pathogenic, we investigated possible alterations in transport regulation and intracellular Ca2+ homeostasis in endoplasmic reticulum (ER). Grp78 is an ER-resident chaperone mediating the unfolded protein response (UPR) and is a key regulator of ER stress transducers. KDEL is a 4-amino-acid retention sequence made of Lys-Asp-Glu-Leu-COO. KDEL is a "resident" sequence as protein residence in ER is consistently associated with KDEL at the C-extremity. Our group used KDEL recognizing anti-Grp78 monoclonal antibody to detect the level of Grp78. We found increased KDEL level in all the transfected cells including cells transfected with PS1 V97L genes, wild-type and the mock. However cells with PS1 V97L mutation expressed a relatively lower KDEL compared with the wild-type and the mock, and a significantly lower Grp78 level compared with the wild-type, the mock and control. These results suggest that PS1 V97L mutation impedes intracellular transport regulation in ER. PS1 V97L mutation mediates increased ER Ca2+ content in human neuroblastoma SH-SY5Y cells. The increased intracellular Ca2+ release is due to depleted Ca2+ storing content of ER but not due to extracellular environment as capacitative Ca2+ entry (CCE) is invariant. PS1 V97L mutation interferes with intracellular Ca2+ homeostasis. Abnormal transport regulation and Ca2+ homeostasis attributed to PS1 V97L mutation may be associated with the pathology of Chinese familial FAD.