Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-12, Vol.103 (51), p.19524-19529
• Main Authors: Landman, Natalie, Jeong, Soon Youn, Shin, Sun Young, Voronov, Sergey V, Serban, Geo, Kang, Min Suk, Park, Myung Kyu, Di Paolo, Gilbert, Chung, Sungkwon, Kim, Tae-Wan
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimers disease; Amyloid beta-Peptides - metabolism; Amyloids; Biological Sciences; Blotting, Western; Cell Line; Cellular biology; Cellular metabolism; Current density; Electrophysiology; Genetic mutation; Genetics; HEK293 cells; Humans; Ion channels; Lipids; Mutation; Mutation - genetics; Neurosciences; Phosphatidylinositols; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Presenilins; Presenilins - genetics; Protein-Serine-Threonine Kinases; TRPM Cation Channels - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0604954103

Phosphatidylinositol 4,5-bisphosphate (PIP₂) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP₂ 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 PIP₂ metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg²⁺-inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP₂, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP₂ turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP₂ closely correlates with 42-residue amyloid β-peptide (Aβ42) levels. Our data suggest that PIP₂ imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic Aβ42 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 PIP₂ may offer a therapeutic approach in Alzheimer's disease.