The Inositol Phosphatase SHIP2 Negatively Regulates Insulin/IGF-I Actions Implicated in Neuroprotection and Memory Function in Mouse Brain
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Impairment of insulin and IGF-I signaling in the brain is one of the causes of dementia associated with diabetes mellitus and Alzheimer’s disease. However, the precise pathological processes are largely unknown. In the present study, we found that SH2-containing inositol 5′-phosphatase 2 (SHIP2), a negative regulator of phosphatidylinositol 3,4,5-trisphosphate-mediated signals, is widely expressed in adult mouse brain. When a dominant-negative mutant of SHIP2 was expressed in cultured neurons, insulin signaling was augmented, indicating physiological significance of endogenous SHIP2 in neurons. Interestingly, SHIP2 mRNA and protein expression levels were significantly increased in the brain of type 2 diabetic db/db mice. To investigate the impact of increased expression of SHIP2 in the brain, we further employed transgenic mice overexpressing SHIP2 and found that increased amounts of SHIP2 induced the disruption of insulin/IGF-I signaling through Akt. Neuroprotective effects of insulin and IGF-I were significantly attenuated in cultured cerebellar granule neurons from SHIP2 transgenic mice. Consistently, terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay demonstrated that the number of apoptosis-positive cells was increased in cerebral cortex of the transgenic mice at an elderly age. Furthermore, SHIP2 transgenic mice exhibited impaired memory performance in the Morris water maze, step-through passive avoidance, and novel-object-recognition tests. Importantly, inhibition of SHIP2 ameliorated the impairment of hippocampal synaptic plasticity and memory formation in db/db mice. These results suggest that SHIP2 is a potent negative regulator of insulin/IGF-I actions in the brain, and excess amounts of SHIP2 may be related, at least in part, to brain dysfunction in insulin resistance with type 2 diabetes.
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Polymorphisms in INPPL1 are associated with type 2 diabetes mellitus.
“polymorphisms in the INPPL1 gene are associated with type 2 diabetes mellitus (T2D)36.”
From A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease (2018) · cites this paper as [36]
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Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., & Greenberg, M. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80405-5 · Cited by 5,689 · see citing works
Critical nodes in signalling pathways: insights into insulin action
Taniguchi, C. M., Emanuelli, B., & Kahn, C. R. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1837 · Cited by 2,760 · see citing works
Regulation of neuronal survival by the serine-threonine protein kinase Akt
Dudek, H., Datta, S. R., Franke, T. F., Birnbaum, M. J., Yao, R., Cooper, G. M., Segal, R. A., Kaplan, D. R., & Greenberg, M. E. (1997) · Science · doi:10.1126/science.275.5300.661 · Cited by 2,436 · see citing works
Risk of dementia in diabetes mellitus: a systematic review
Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C., & Scheltens, P. (2006) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70284-2 · Cited by 2,187 · see citing works
Steen, E., Terry, B. M., J. Rivera, E., Cannon, J. L., Neely, T. R., Tavares, R., Xu, X. J., Wands, J. R., & de la Monte, S. M. (2005) · Journal of Alzheimer's Disease · doi:10.3233/jad-2005-7107 · Cited by 1,703 · see citing works
The glamour and gloom of glycogen synthase kinase-3
Jope, R. S., & Johnson, G. V. W. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.12.004 · Cited by 1,522 · see citing works
Recognition memory and the medial temporal lobe: a new perspective
Squire, L. R., Wixted, J. T., & Clark, R. E. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2154 · Cited by 1,028 · see citing works
Lucas, J. J., Hernández, F., Gómez‐Ramos, P., Morán, M. A., Hen, R., & Avila, J. (2001) · The EMBO Journal · doi:10.1093/emboj/20.1.27 · Cited by 903 · see citing works
Moloney, A. M., Griffin, R. J., Timmons, S., O’Connor, R., Ravid, R., & O’Neill, C. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.04.002 · Cited by 764 · see citing works
Stranahan, A. M., Arumugam, T. V., Cutler, R. G., Lee, K. M., Egan, J. M., & Mattson, M. P. (2008) · Nature Neuroscience · doi:10.1038/nn2055 · Cited by 610 · see citing works
Reger, M. A., Watson, G. S., Green, P. S., Baker, L. D., Cholerton, B., Fishel, M. A., Plymate, S. R., Cherrier, M. M., Schellenberg, G. D., Frey, W. H., et al. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-13309 · Cited by 518 · see citing works
Insulin and the insulin receptor in experimental models of learning and memory
Zhao, W., Chen, H., Quon, M. J., & Alkon, D. L. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.02.045 · Cited by 503 · see citing works
Craft, S. (2007) · Current Alzheimer Research · doi:10.2174/156720507780362137 · Cited by 487 · see citing works
Insulin signaling in the central nervous system: Learning to survive
van der Heide, L. P., Ramakers, G. M. J., & Smidt, M. P. (2006) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2006.06.003 · Cited by 444 · see citing works
Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents
Li, X.-L., Aou, S., Oomura, Y., Hori, N., Fukunaga, K., & Hori, T. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00162-8 · Cited by 440 · see citing works
Linseman, D. A., Butts, B. D., Precht, T. A., Phelps, R. A., Le, S. S., Laessig, T. A., Bouchard, R. J., Florez‐McClure, M. L., & Heidenreich, K. A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2057-04.2004 · Cited by 370 · see citing works
Cyclic AMP Promotes Neuronal Survival by Phosphorylation of Glycogen Synthase Kinase 3β
Li, M., Wang, X., Meintzer, M. K., Laessig, T. A., Birnbaum, M. J., & Heidenreich, K. A. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.24.9356-9363.2000 · Cited by 363 · see citing works
Self-citationIntracerebroventricular insulin enhances memory in a passive-avoidance task
Park, C. R., Seeley, R. J., Craft, S., & WOODS, S. (2000) · Physiology & Behavior · doi:10.1016/s0031-9384(99)00220-6 · Cited by 343 · see citing works
Signaling by insulin-like growth factor 1 in brain
Bondy, C. A., & Cheng, C. M. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.02.042 · Cited by 323 · see citing works
Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart
Benedict, C., Hallschmid, M., Schmitz, K., Schultes, B., Ratter, F., Fehm, H. L., Born, J., & Kern, W. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301193 · Cited by 302 · see citing works
D’Mello, S. R., Borodezt, K., & Soltoff, S. P. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-05-01548.1997 · Cited by 286 · see citing works
Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes
Li, Z.-G., Zhang, W., & Sima, A. A. F. (2007) · Diabetes · doi:10.2337/db07-0171 · Cited by 265 · see citing works
Engel, T., Hernández, F., Ávila, J., & Lucas, J. J. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0604-06.2006 · Cited by 261 · see citing works
Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity
Sleeman, M. W., Wortley, K. E., Lai, K. V., Gowen, L. C., Kintner, J., Kline, W. O., García, K., Stitt, T. N., Yancopoulos, G. D., Wiegand, S. J., et al. (2005) · Nature Medicine · doi:10.1038/nm1178 · Cited by 255 · see citing works
Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging
Sonntag, W. E., Ramsey, M. M., & Carter, C. S. (2005) · Ageing Research Reviews · doi:10.1016/j.arr.2005.02.001 · Cited by 254 · see citing works
Insulin/IGF-like signalling, the central nervous system and aging
Broughton, S., & Partridge, L. (2009) · Biochemical Journal · doi:10.1042/bj20082102 · Cited by 228 · see citing works
Zheng, W., & Quirion, R. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02350.x · Cited by 225 · see citing works
Adiposity, Type 2 Diabetes, and Alzheimer's Disease
Luchsinger, J. A., & Gustafson, D. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1022 · Cited by 212 · see citing works
Stubley, L., Harding, J. W., & Wright, J. W. (1996) · Brain Research · doi:10.1016/0006-8993(95)01589-2 · Cited by 211 · see citing works
Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies
Gerozissis, K. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.01.050 · Cited by 197 · see citing works
Taylor, V., Wong, M. P., Brandts, C., Reilly, L., Dean, N. M., Cowsert, L. M., Moodie, S. A., & Stokoe, D. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.18.6860-6871.2000 · Cited by 182 · see citing works
Wada, T., Sasaoka, T., Funaki, M., Hori, H., Murakami, S., Ishiki, M., Haruta, T., Asano, T., Ogawa, W., Ishihara, H., et al. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.5.1633-1646.2001 · Cited by 172 · see citing works
Self-citationWang, D., Noda, Y., Zhou, Y., Mouri, A., Mizoguchi, H., Nitta, A., Chen, W., & Nabeshima, T. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301256 · Cited by 148 · see citing works
Kelly, A. M., & Lynch, M. A. (2000) · Neuropharmacology · doi:10.1016/s0028-3908(99)00169-0 · Cited by 145 · see citing works
Ishihara, H., Sasaoka, T., Hori, H., Wada, T., Hirai, H., Haruta, T., Langlois, W. J., & Kobayashi, M. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0888 · Cited by 132 · see citing works
Self-citationCanu, N., Tufi, R., Serafino, A., Amadoro, G., Ciotti, M. T., & Calissano, P. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02956.x · Cited by 129 · see citing works
Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice
Tsuneki, H., Murata, S., Anzawa, Y., Soeda, Y., Tokai, E., Wada, T., Kimura, I., Yanagisawa, M., Sakurai, T., & Sasaoka, T. (2008) · Diabetologia · doi:10.1007/s00125-008-0929-8 · Cited by 124 · see citing works
Self-citationLeptin Regulates AMPA Receptor Trafficking via PTEN Inhibition
Moult, P. R., Cross, A., Santos, S. D., Carvalho, A. L., Lindsay, Y. E., Connolly, C. N., Irving, A. J., Leslie, N. R., & Harvey, J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.3614-09.2010 · Cited by 123 · see citing works
Lipid phosphatases as drug discovery targets for type 2 diabetes
Lazar, D. F., & Saltiel, A. R. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2007 · Cited by 113 · see citing works
Linking type 2 diabetes and Alzheimer's disease
Han, W., & Li, C. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002555107 · Cited by 104 · see citing works
Hori, H., Sasaoka, T., Ishihara, H., Wada, T., Murakami, S., Ishiki, M., & Kobayashi, M. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2387 · Cited by 88 · see citing works
Self-citationSuwa, A., Yamamoto, T. S., Sawada, A., Minoura, K., Hosogai, N., Tahara, A., Kurama, T., Shimokawa, T., & Aramori, I. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00358.x · Cited by 87 · see citing works
Diabetes and brain aging: Epidemiologic evidence
Launer, L. J. (2005) · Current Diabetes Reports · doi:10.1007/s11892-005-0069-1 · Cited by 85 · see citing works
Lipid phosphatases as a possible therapeutic target in cases of type 2 diabetes and obesity
Sasaoka, T., Wada, T., & Tsuneki, H. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.06.001 · Cited by 72 · see citing works
Self-citationBléro, D., Smedt, F. D., Pesesse, X., Paternotte, N., Moreau, C., Payrastre, B., & Erneux, C. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.4639 · Cited by 71 · see citing works
Aoki, K., Nakamura, T., Inoue, T., Meyer, T., & Matsuda, M. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200609017 · Cited by 65 · see citing works
Yasuda, M., Fukuchi, M., Tabuchi, A., Kawahara, M., Tsuneki, H., Azuma, Y., Chiba, Y., & Tsuda, M. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04851.x · Cited by 63 · see citing works
Self-citationKagawa, S., Soeda, Y., Ishihara, H., Oya, T., Sasahara, M., Yaguchi, S., Oshita, R., Wada, T., Tsuneki, H., & Sasaoka, T. (2007) · Endocrinology · doi:10.1210/en.2007-0820 · Cited by 63 · see citing works
Self-citationArtola, A. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.11.084 · Cited by 57 · see citing works
Impaired Central Insulin Response in Aged Wistar Rats: Role of Adiposity
Frutos, M. G.-S., Fernández‐Agulló, T., Solís, A. J. D., Andrés, A., Arribas, C., Carrascosa, J. M., & Ros, M. (2007) · Endocrinology · doi:10.1210/en.2007-0543 · Cited by 48 · see citing works
Jones, A., Kulozik, P., Ostertag, A., & Herzig, S. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0973 · Cited by 47 · see citing works
Schurmans, S., Carrió, R., Behrends, J., Pouillon, V., Merino, J., & Clément, S. (1999) · Genomics · doi:10.1006/geno.1999.5995 · Cited by 34 · see citing works
Muraille, É., Dassesse, D., Vanderwinden, J., Cremer, H., Rogister, B., Erneux, C., & Schiffmann, S. N. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00240-8 · Cited by 20 · see citing works
Familiarity and Recollection in the Medial Temporal Lobe
Kafkas, A., & Migo, E. M. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5874-08.2009 · Cited by 13 · see citing works
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Mostafavi, S., Gaiteri, C., Sullivan, S. E., White, C. C., Tasaki, S., Xu, J., Taga, M., Klein, H.-U., Patrick, E., Komashko, V., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0154-9 · Cited by 509 · see citing works
- Authors
- Soeda, Y., Tsuneki, H., Muranaka, H., Mori, N., Hosoh, S., Ichihara, Y., Kagawa, S., Wang, X., Toyooka, N., Takamura, Y., Uwano, T., Nishijo, H., Wada, T., & Sasaoka, T.
- Affiliations
- Department of Clinical Pharmacology (Y.S., H.T., H.M., N.M., S.H., Y.I., S.K., T.W., T.S.), Toyama 930-0194, Japan
- University of Toyama (JP)
- Corresponding author
- Wada, Tsutomu
- Sasaoka, Toshiyasu
- ORCID
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2010-10-01
- Volume
- 24
- Issue
- 10
- Pages
- 1965-1977
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC5417391
- OpenAlex
- W2083208834
- Cited by
- 38
- References
- 54
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 1 · 2013: 8 · 2012: 3
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Naito Foundation
- Takeda Science Foundation
- Novo Nordisk
- Smoking Research Foundation
- Novo Nordisk Pharma
- Japan Society for the Promotion of Science (22240051)
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- SHIP2, inositol polyphosphate 5-phosphatase, insulin signaling, IGF-1 signaling, insulin resistance, type 2 diabetes, brain, neuroprotection, memory impairment, apoptosis, Akt, PI3K/AKT/mTOR pathway, cerebellar granule cells, hippocampal synaptic plasticity, db/db mice, Alzheimer's disease, dementia
- MeSH terms
- Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Aging, Animals, Brain, Cells, Cultured, Diabetes Mellitus, Type 2, Enzyme Inhibitors, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Memory, Memory Disorders, Mice, Mutant Strains, Mice, Transgenic, Neuronal Plasticity, Neurons, Phosphoric Monoester Hydrolases, Signal Transduction, Neuroprotective Agents, Mice
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