부산대학교 도서관

Phosphatidylinositol 4,5-bisphosphate (PI[P.sub.2]) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PI[P.sub.2] metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PI[P.sub.2] metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated [Mg.sup.2+]-inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PI[P.sub.2], a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PI[P.sub.2] turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PI[P.sub.2] closely correlates with 42-residue amyloid [beta]-peptide (A[beta]42) levels. Our data suggest that PI[P.sub.2] imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic A[beta]42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PI[P.sub.2] may offer a therapeutic approach in Alzheimer's disease. [beta]-amyloid precursor protein | channel | secretase | transient receptor potential melastatin 7 (TRPM7) | capacitative calcium entry