Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism
Open accessAbstract
Synaptic dysfunction caused by oligomeric assemblies of amyloid-beta peptide (Abeta) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric Abeta decreases the level of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), a phospholipid that regulates key aspects of neuronal function. The destabilizing effect of Abeta on PtdIns(4,5)P2 metabolism was Ca2+-dependent and was not observed in neurons that were derived from mice that are haploinsufficient for Synj1. This gene encodes synaptojanin 1, the main PtdIns(4,5)P2 phosphatase in the brain and at the synapses. We also found that the inhibitory effect of Abeta on hippocampal long-term potentiation was strongly suppressed in slices from Synj1+/- mice, suggesting that Abeta-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P2 balance in the brain.
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Altered PI(4,5)P2 metabolism is linked to Aβ toxicity.
“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 [94]
The effect of Aβ oligomers on PI(4,5)P2 levels is attenuated in primary neurons from mice with loss of one copy of Synj1.
“This effect of Aβ oligomers was attenuated in primary neurons from mice with loss of one copy of Synj1 [94].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [94]
Treatment of primary cortical neurons with oligomeric Aβ (but not monomeric or fAβ) induces a rapid reduction in PI(4,5)P2 levels that is reversible with removal of the treated Aβ.
“Treatment of primary cortical neurons with oligomeric Aβ (but not monomeric or fAβ) induces a rapid reduction in PI(4,5)P2 levels that is reversible with removal of the treated Aβ [94].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [94]
The C-terminus of SHIP1 contains a NPxY motif that can bind proteins containing ITIM/ITAM, PTB or SH2 domains, and a proline-rich PxxP motif that contains SH3-binding domains.
“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 [94]
Cites
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · see citing works
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291 · see citing works
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · see citing works
Aβ Oligomers – a decade of discovery
Walsh, D. M., & Selkoe, D. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04426.x · Cited by 1,938 · see citing works
Shankar, G. M., Bloodgood, B. L., Townsend, M., Walsh, D. M., Selkoe, D. J., & Sabatini, B. L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4970-06.2007 · Cited by 1,592 · see citing works
Regulation of NMDA receptor trafficking by amyloid-β
Snyder, E. M., Nong, Y., Almeida, C. G., Paul, S., Moran, T., Choi, E. Y., Nairn, A. C., Salter, M. W., Lombroso, P. J., Gouras, G. K., et al. (2005) · Nature Neuroscience · doi:10.1038/nn1503 · Cited by 1,561 · cited 1× · see citing works
“Consistent with these studies, oligomers of Aβ, particularly Aβ42, have been shown to directly affect synaptic plasticity and trigger the loss of synaptic dendritic spine”
ResultOligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability
Dahlgren, K. N., Manelli, A. M., Stine, W. B., Baker, L. K., Krafft, G. A., & LaDu, M. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201750200 · Cited by 1,452 · see citing works
Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo
Klyubin, I., Walsh, D. M., Lemere, C. A., Cullen, W. K., Shankar, G. M., Betts, V., Spooner, E. T., Jiang, L., Anwyl, R., Selkoe, D. J., et al. (2005) · Nature Medicine · doi:10.1038/nm1234 · Cited by 489 · see citing works
Gong, B., Vitolo, O. V., Trinchese, F., Liu, S., Shelanski, M., & Arancio, O. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22831 · Cited by 442 · see citing works
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. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604954103 · Cited by 149 · see citing works
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Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · see citing works
Deleterious Effects of Amyloid β Oligomers Acting as an Extracellular Scaffold for mGluR5
Renner, M., Lacor, P. N., Velasco, P. T., Xu, J., Contractor, A., Klein, W. L., & Triller, A. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.029 · Cited by 468 · see citing works
Down syndrome and Alzheimer's disease: common pathways, common goals
Hartley, D., Blumenthal, T., Carrillo, M., DiPaolo, G., Esralew, L., Gardiner, K., Granholm, A.-C., Iqbal, K., Krams, M., Lemere, C., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.10.007 · Cited by 290 · see citing works
Morel, E., Chamoun, Z., Lasiecka, Z. M., Chan, R. B., Williamson, R. L., Vetanovetz, C., Dall’Armi, C., Simoes, S., Point Du Jour, K. S., McCabe, B. D., et al. (2013) · Nature Communications · doi:10.1038/ncomms3250 · Cited by 222 · see citing works
Self-citationThal, D. R., Griffin, W. S. T., & Braak, H. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00411.x · Cited by 134 · see citing works
Terzioglu, G., & Young-Pearse, T. L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00674-9 · Cited by 95 · see citing works
Desale, S. E., & Chinnathambi, S. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00715-0 · Cited by 81 · see citing works
Synaptophysin and Synaptojanin-1 in Down Syndrome are Differentially Affected by Alzheimer's Disease
Martin, S. B., Dowling, A. L. S., Lianekhammy, J., Lott, I. T., Doran, E., Murphy, M. P., Beckett, T. L., Schmitt, F. A., & Head, E. (2014) · Journal of Alzheimer's Disease · doi:10.3233/jad-140795 · Cited by 64 · see citing works
Ernest James Phillips, T., & Maguire, E. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.652593 · Cited by 33 · see citing works
- Authors
- Berman, D. E., Dall'Armi, C., Voronov, S. V., McIntire, L. B. J., Zhang, H., Moore, A. Z., Staniszewski, A., Arancio, O., Kim, T.-W., & Di Paolo, G.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Kim, Tae-Wan
- Venue
- Nature Neuroscience
- Published
- 2008-04-06
- Volume
- 11
- Issue
- 5
- Pages
- 547-554
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2532986
- OpenAlex
- W2143830585
- Cited by
- 199
- References
- 10
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 6 · 2023: 10 · 2022: 3 · 2021: 8 · 2020: 14 · 2019: 13 · 2018: 6 · 2017: 9 · 2016: 15 · 2015: 9 · 2014: 15 · 2013: 13 · 2012: 19
- FWCI
- 10.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS056049, R01NS043467, R01NS056049, R01NS049442, NS043467, NS049442)
- National Center for Complementary and Integrative Health (R01AT002643, AT002643)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD047733, R21HD047733)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta oligomers, phosphatidylinositol 4,5-bisphosphate, SYNJ1, synaptic dysfunction, Alzheimer's disease, calcium-dependent signaling, hippocampal long-term potentiation, cortical neurons
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Cerebral Cortex, Heterozygote, Hippocampus, Mice, Neurologic Mutants, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Organ Culture Techniques, Type C Phospholipases, Phosphoric Monoester Hydrolases, Down-Regulation, Amyloid beta-Peptides, PC12 Cells, Phosphatidylinositol 4,5-Diphosphate, Lipid Metabolism, Mice, Rats
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