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Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism
Open accessAbstract
Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP 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 PIP 2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg 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 PIP 2 , a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP 2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP 2 closely correlates with 42-residue amyloid β-peptide (Aβ42) levels. Our data suggest that PIP 2 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 PIP 2 may offer a therapeutic approach in Alzheimer's disease.
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“Familial AD PSEN1 mutations result in disrupted metabolism of PI(4,5)P2 [95] and PI(4,5)P2 has been reported to be reduced in the AD brain [93].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [95]
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“Altered PI(4,5)P2 metabolism has been linked to Aβ toxicity [93–95].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [95]
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“The C-terminus of SHIP1 contains a NPxY motif, which can bind to proteins containing immunoreceptor tyrosine inhibitory motifs (ITIM)/immunoreceptor tyrosine activating motifs (ITAM), phosphotyrosine-binding (PTB) or SH2 domains, as well as a proline-rich PxxP motif that contains SH3-binding domains [47, 93–98] (Fig. 2).”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [95]
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Cites
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Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
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A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
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Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
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Linking lipids to Alzheimer's disease: cholesterol and beyond
Di Paolo, G., & Kim, T.-W. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3012 · Cited by 972
Self-citationPresenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria
Area-Gomez, E., de Groof, A. J. C., Boldogh, I., Bird, T. D., Gibson, G. E., Koehler, C. M., Yu, W. H., Duff, K. E., Yaffe, M. P., Pon, L. A., et al. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.090219 · Cited by 369
Brain lipidomics: From functional landscape to clinical significance
Yoon, J. H., Seo, Y., Jo, Y. S., Lee, S., Cho, E., Cazenave-Gassiot, A., Shin, Y.-S., Moon, M. H., An, H. J., Wenk, M. R., et al. (2022) · Science Advances · doi:10.1126/sciadv.adc9317 · Cited by 324
Wunderlich, P., Glebov, K., Kemmerling, N., Tien, N. T., Neumann, H., & Walter, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.517540 · Cited by 296
Understanding phosphoinositides: rare, dynamic, and essential membrane phospholipids
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Metadata
- Authors
- Landman, N., Jeong, S. Y., Shin, S. Y., Voronov, S. V., Serban, G., Kang, M. S., Park, M. K., Di Paolo, G., Chung, S., & Kim, T.-W.
- Affiliations
- Columbia University Irving Medical Center (US)
- Sungkyunkwan University (KR)
- Department of Pathology, and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-12-19
- Volume
- 103
- Issue
- 51
- Pages
- 19524-19529
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1748258
- OpenAlex
- W2047442659
- Cited by
- 149
- References
- 50
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 6 · 2021: 1 · 2020: 12 · 2019: 6 · 2018: 3 · 2017: 8 · 2016: 5 · 2015: 8 · 2014: 9 · 2013: 14 · 2012: 13
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- National Institutes of Health
- Samsung
- National Institute of Neurological Disorders and Stroke (R01NS043467, F31NS051186, NS43467, NS51186)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD047733, R21HD047733)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- presenilin mutations, familial Alzheimer's disease, phosphatidylinositol 4,5-bisphosphate, TRPM7, ion channel dysfunction, amyloid-beta 42, lipid turnover, Alzheimer's disease pathogenesis, therapeutic target
- MeSH terms
- Alzheimer Disease, Cell Line, Electrophysiology, Humans, Mutation, Phosphorylation, Blotting, Western, Amyloid beta-Peptides, Protein Serine-Threonine Kinases, Phosphotransferases (Alcohol Group Acceptor), TRPM Cation Channels, Presenilins
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