Leptin prevents aberrant targeting of tau to hippocampal synapses via PI 3 kinase driven inhibition of GSK3β
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Amyloid‐β (Aβ) and hyper‐phosphorylated tau are key hallmarks of Alzheimer's disease (AD), with an accumulation of both proteins linked to hippocampal synaptic dysfunction. Recent evidence indicates that Aβ drives mis‐localisation of tau from axons to synapses, resulting in AMPA receptor (AMPAR) internalisation and impaired excitatory synaptic function. These tau‐driven synaptic impairments are thought to underlie the cognitive deficits in AD. Consequently, limiting the synapto‐toxic effects of tau may prevent AD‐related cognitive deficits. Increasing evidence links leptin dysfunction with higher AD risk, and numerous studies have identified neuroprotective properties of leptin in AD models of Aβ‐induced toxicity. However, it is unclear if leptin protects against tau‐related synaptic dysfunction. Here we show that Aβ 1‐42 significantly increases dendritic and synaptic levels of tau and p‐tau in hippocampal neurons, and these effects were blocked by leptin. In accordance with GSK‐3β being involved in tau phosphorylation, the protective effects of leptin involve PI 3‐kinase (PI3K) activation and inhibition of GSK‐3β. Aβ 1‐42 ‐driven synaptic targeting of tau was associated with the removal of GluA1‐containing AMPARs from synapses, which was also inhibited by leptin‐driven inhibition of GSK‐3β. Direct application of oligomeric tau to hippocampal neurons caused internalisation of GluA1‐containing AMPARs and this effect was blocked by prior application of leptin. Similarly, leptin prevented the ability of tau to block induction of activity‐dependent long‐term potentiation (LTP) at hippocampal SC‐CA1 synapses. These findings increase our understanding of the neuroprotective actions of leptin in the early pre‐clinical stages of AD and further validate the leptin system as a therapeutic target in AD. image
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Leptin counteracts Aβ pathology and tau phosphorylation to prevent synaptic dysfunction.
“leptin is involved in counteracting Aβ pathology and tau phosphorylation to prevent synaptic dysfunction.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [589]
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1 retracted
Marwarha, G., Dasari, B., Prasanthi, J. R. P., Schommer, J., & Ghribi, O. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1298 · Cited by 139 · see citing works
RetractedWalsh, 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
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., et al. (2008) · Nature Medicine · doi:10.1038/nm1782 · Cited by 3,685 · see citing works
Obesity and the regulation of energy balance
Spiegelman, B. M., & Flier, J. S. (2001) · Cell · doi:10.1016/s0092-8674(01)00240-9 · Cited by 2,398 · see citing works
Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892 · see citing works
Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
Ittner, L. M., Ke, Y. D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., Wölfing, H., Chieng, B. C., Christie, M. J., Napier, I. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.036 · Cited by 1,821 · see citing works
Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., Pitstick, R., Carlson, G. A., Lanier, L. M., Yuan, L.-L., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.030 · Cited by 1,118 · see citing works
Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing
Cunnane, S. C., Trushina, E., Morland, C., Prigione, A., Casadesus, G., Andrews, Z. B., Beal, M. F., Bergersen, L. H., Brinton, R. D., de la Monte, S., et al. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0072-x · Cited by 1,003 · see citing works
Self-citationLi, S., Hong, S., Shepardson, N. E., Walsh, D. M., Shankar, G. M., & Selkoe, D. (2009) · Neuron · doi:10.1016/j.neuron.2009.05.012 · Cited by 972 · see citing works
Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau.
Drechsel, D. N., Hyman, A. A., Cobb, M. H., & Kirschner, M. W. (1992) · Molecular Biology of the Cell · doi:10.1091/mbc.3.10.1141 · Cited by 971 · see citing works
Bramblett, G. T., Goedert, M., Jakes, R., Merrick, S. E., Trojanowski, J. Q., & Lee, V. M. Y. (1993) · Neuron · doi:10.1016/0896-6273(93)90057-x · Cited by 903 · see citing works
Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., et al. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14112 · Cited by 903 · see citing works
Jin, M., Shepardson, N., Yang, T., Chen, G., Walsh, D., & Selkoe, D. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017033108 · Cited by 876 · see citing works
Gong, C., & Iqbal, K. (2008) · Current Medicinal Chemistry · doi:10.2174/092986708785909111 · Cited by 649 · see citing works
Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau
Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Kiritoshi, T., Neugebauer, V., Jackson, G. R., & Kayed, R. (2012) · Scientific Reports · doi:10.1038/srep00700 · Cited by 502 · 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
Association of Plasma Leptin Levels With Incident Alzheimer Disease and MRI Measures of Brain Aging
Lieb, W. (2009) · JAMA · doi:10.1001/jama.2009.1836 · Cited by 428 · see citing works
Leptin Enhances NMDA Receptor Function and Modulates Hippocampal Synaptic Plasticity
Shanley, L. J., Irving, A. J., & Harvey, J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-24-j0001.2001 · Cited by 416 · see citing works
Self-citationPhosphorylation of different tau sites during progression of Alzheimer’s disease
Neddens, J., Temmel, M., Flunkert, S., Kerschbaumer, B., Hoeller, C., Loeffler, T., Niederkofler, V., Daum, G., Attems, J., & Hutter-Paier, B. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0557-6 · Cited by 384 · see citing works
C-terminal inhibition of tau assembly in vitro and in Alzheimer’s disease
Abraha, A., Ghoshal, N., Gamblin, T. C., Cryns, V. L., Berry, R. W., Kuret, J., & Binder, L. I. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.21.3737 · Cited by 326 · see citing works
Obesity‐related leptin regulates Alzheimer's Aβ
Fewlass, D. C., Noboa, K., Pi‐Sunyer, F. X., Johnston, J. M., Yan, S. D., & Tezapsidis, N. (2004) · The FASEB Journal · doi:10.1096/fj.04-2572com · Cited by 308 · see citing works
Aβ1-42 inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β
Jo, J., Whitcomb, D. J., Olsen, K. M., Kerrigan, T. L., Lo, S.-C., Bru-Mercier, G., Dickinson, B., Scullion, S., Sheng, M., Collingridge, G., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2785 · Cited by 305 · see citing works
Oomura, Y., Hori, N., Shiraishi, T., Fukunaga, K., Takeda, H., Tsuji, M., Matsumiya, T., Ishibashi, M., Aou, S., Li, X. L., et al. (2006) · Peptides · doi:10.1016/j.peptides.2006.07.001 · Cited by 284 · see citing works
Dendritic Tau in Alzheimer’s Disease
Ittner, A., & Ittner, L. M. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.003 · Cited by 278 · see citing works
Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory
Fà, M., Puzzo, D., Piacentini, R., Staniszewski, A., Zhang, H., Baltrons, M. A., Puma, D. D. L., Chatterjee, I., Li, J., Saeed, F., et al. (2016) · Scientific Reports · doi:10.1038/srep19393 · Cited by 274 · see citing works
Anderson, W. W., & Collingridge, G. L. (2007) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2006.12.018 · Cited by 258 · see citing works
Wagner, U., Utton, M. A., Gallo, J., & Miller, C. C. J. (1996) · Journal of Cell Science · doi:10.1242/jcs.109.6.1537 · Cited by 255 · see citing works
Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro
Garza, J. C., Guo, M., Zhang, W., & Lu, X. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800053200 · Cited by 236 · see citing works
Leptin Reduces Pathology and Improves Memory in a Transgenic Mouse Model of Alzheimer's Disease
Greco, S. J., Bryan, K. J., Sarkar, S., Zhu, X., Smith, M. A., Ashford, J. W., Johnston, J. M., Tezapsidis, N., & Casadesús, G. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1308 · Cited by 218 · see citing works
Guo, Z., Jiang, H., Xu, X. Z. S., Duan, W., & Mattson, M. P. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703753200 · Cited by 202 · see citing works
Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo
Wayner, M. J., Armstrong, D. L., Phelix, C. F., & Oomura, Y. (2004) · Peptides · doi:10.1016/j.peptides.2004.03.018 · Cited by 190 · see citing works
Leptin promotes rapid dynamic changes in hippocampal dendritic morphology
O’Malley, D., MacDonald, N., Mizielinska, S., Connolly, C. N., Irving, A. J., & Harvey, J. (2007) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2007.05.001 · Cited by 178 · see citing works
Self-citationLTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent
Puzzo, D., Piacentini, R., Fá, M., Gulisano, W., Li Puma, D. D., Staniszewski, A., Zhang, H., Tropea, M. R., Cocco, S., Palmeri, A., et al. (2017) · eLife · doi:10.7554/elife.26991 · Cited by 172 · see citing works
Leroy, K., Ando, K., Laporte, V., Dedecker, R., Suain, V., Authelet, M., Héraud, C., Pierrot, N., Yilmaz, Z., Octave, J.-N., et al. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2012.08.012 · Cited by 161 · see citing works
Circulating Leptin Levels and Weight Loss in Alzheimer’s Disease Patients
Power, D. A., Noel, J., Collins, R., & O’Neill, D. J. (2001) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000051252 · Cited by 149 · see citing works
Antiapoptotic Effects of Leptin in Human Neuroblastoma Cells
Russo, V. C., Metaxas, S., Kobayashi, K., Harris, M. A., & Werther, G. A. (2004) · Endocrinology · doi:10.1210/en.2003-1767 · Cited by 146 · see citing works
Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance
Bonda, D., Stone, J. G., Torres, S. L., Siedlak, S. L., Perry, G. L., Kryscio, R. J., Jicha, G. A., Casadesús, G., Smith, M. A., Zhu, X., et al. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12380 · Cited by 145 · see citing works
Miller, E. C., Teravskis, P. J., Dummer, B. W., Zhao, X., Huganir, R. L., & Liao, D. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12507 · Cited by 131 · see citing works
Leptin 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
Self-citationLeptin inhibits glycogen synthase kinase-3β to prevent tau phosphorylation in neuronal cells
Greco, S. J., Sarkar, S., Casadesús, G., Zhu, X., Smith, M. A., Ashford, J. W., Johnston, J. M., & Tezapsidis, N. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.03.066 · Cited by 119 · see citing works
Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β
Doherty, G. H., Beccano-Kelly, D. A., Yan, S. D., Gunn‐Moore, F. J., & Harvey, J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.08.003 · Cited by 115 · see citing works
Self-citationOndrejčák, T., Klyubin, I. V., Corbett, G. T., Fraser, G. M., Hong, W., Mably, A. J., Gardener, M. J., Hammersley, J., Perkinton, M. S., Billinton, A., et al. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1700-18.2018 · Cited by 102 · see citing works
Adipocytokines and CD34+ Progenitor Cells in Alzheimer's Disease
Bigalke, B., Schreitmüller, B., Sopova, K., Paul, A., Stransky, E., Gawaz, M., Stellos, K., & Laske, C. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020286 · Cited by 87 · see citing works
Leptin Induces Hippocampal Synaptogenesis via CREB-Regulated MicroRNA-132 Suppression of p250GAP
Dhar, M., Zhu, M., Impey, S., Lambert, T. J., Bland, T., Karatsoreos, I. N., Nakazawa, T., Appleyard, S. M., & Wayman, G. A. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1332 · Cited by 83 · see citing works
Neuroprotective effects of leptin in the context of obesity and metabolic disorders
Davis, C., Mudd, J., & Hawkins, M. A. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.04.012 · Cited by 83 · see citing works
Hu, N., Corbett, G. T., Moore, S., Klyubin, I. V., O’Malley, T. T., Walsh, D. M., Livesey, F. J., & Rowan, M. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.04.040 · Cited by 81 · see citing works
Leptin-Induced Spine Formation Requires TrpC Channels and the CaM Kinase Cascade in the Hippocampus
Dhar, M., Wayman, G. A., Zhu, M., Lambert, T. J., Davare, M. A., & Appleyard, S. M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2868-13.2014 · Cited by 67 · see citing works
McGregor, G., & Harvey, J. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00340 · Cited by 67 · see citing works
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Moult, P. R., & Harvey, J. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.06.021 · Cited by 66 · see citing works
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Stranahan, A. M., & Mattson, M. P. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.01.004 · Cited by 62 · see citing works
Rui, Y., Gu, J., Yu, K., Hartzell, H. C., & Zheng, J. Q. (2010) · Molecular Brain · doi:10.1186/1756-6606-3-10 · Cited by 61 · see citing works
Leptin and ghrelin prevent hippocampal dysfunction induced by Aβ oligomers.
Martins, I., Gomes, S., Costa, R. O., Otvos, L., Oliveira, C. R., Resende, R., & Pereira, C. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.02.062 · Cited by 57 · see citing works
Luo, X., McGregor, G., Irving, A. J., & Harvey, J. (2015) · eNeuro · doi:10.1523/eneuro.0007-15.2015 · Cited by 47 · see citing works
Self-citationIrving, A. J., & Harvey, J. (2021) · Progress in Lipid Research · doi:10.1016/j.plipres.2021.101098 · Cited by 44 · see citing works
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Malekizadeh, Y., Holiday, A., Redfearn, D., Ainge, J. A., Doherty, G. H., & Harvey, J. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw272 · Cited by 43 · see citing works
Self-citationPrikas, E., Parić, E., Asih, P. R., Stefanoska, K., Stefen, H., Fath, T., Poljak, A., & Ittner, A. (2022) · The EMBO Journal · doi:10.15252/embj.2021110242 · Cited by 39 · see citing works
Magalhães, C. A., Carvalho, M. G., Sousa, L. P., Caramelli, P., & Gomes, K. B. (2015) · Clinica Chimica Acta · doi:10.1016/j.cca.2015.08.009 · Cited by 33 · see citing works
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Mondragón‐Rodríguez, S., Salgado, H., & Peña‐Ortega, F. (2020) · Neural Plasticity · doi:10.1155/2020/2960343 · Cited by 32 · see citing works
McGregor, G., Clements, L., Farah, A., Irving, A. J., & Harvey, J. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.05.007 · Cited by 29 · see citing works
Self-citationTeravskis, P. J., Oxnard, B. R., Miller, E. C., Kemper, L. J., Ashe, K. H., & Liao, D. (2019) · The Journal of Physiology · doi:10.1113/jp277459 · Cited by 29 · see citing works
Clements, L., & Harvey, J. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14880 · Cited by 25 · see citing works
Self-citationClements, L., Alexander, A., Hamilton, K., Irving, A. J., & Harvey, J. (2023) · Molecular Brain · doi:10.1186/s13041-023-01003-3 · Cited by 17 · see citing works
Self-citationDoherty, G. H., Holiday, A., Malekizadeh, Y., Manolescu, C., Duncan, S., Flewitt, I., Hamilton, K., MacLeod, B., Ainge, J. A., & Harvey, J. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15733 · Cited by 16 · see citing works
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
- Authors
- Hamilton, K., Morrow, K., Markantoni, E., & Harvey, J.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Harvey, Jenni
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2023-10-11
- Volume
- 167
- Issue
- 4
- Pages
- 520-537
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W4387563071
- Cited by
- 10
- References
- 63
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neurochemistry (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by-nc)
- Funders
- Alzheimer's Society (AS‐PhD‐18‐007)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- leptin, tau phosphorylation, amyloid-beta, Alzheimer's disease, hippocampus, phosphatidylinositol 3-kinase, GSK3β, GluR1, long-term potentiation, synaptic dysfunction, neuroprotection, therapeutic target
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Hippocampus, Humans, Phosphorylation, Synapses, Amyloid beta-Peptides, tau Proteins, Phosphatidylinositol 3-Kinases, Leptin
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