The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Neuronal IGF‐1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease
Abstract
Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin‐like growth factor (IGF)‐1 receptor (IGF‐1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF‐1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP SW , Tg2576 mice) as a model for AD with mice deficient for either IRS‐2, neuronal IGF‐1R (nIGF‐1R −/− ), or neuronal insulin receptor (nIR −/− ), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS‐2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays β‐amyloid (Aβ) accumulation. Analysis of APP metabolism suggested that delayed Aβ accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS‐2‐mediated disease protection, we analyzed mice with nIGF‐1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF‐1R −/− Tg2576 mice were protected from premature death in the presence of decreased Aβ accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF‐1/IRS‐2 signaling prevents premature death and delays amyloid accumulation in a model of AD.—Freude, S., Hettich, M. M., Schumann, C., Stohr, O., Koch, L., Kohler, C., Udelhoven, M., Leeser, U., Müller, M., Kubota, N., Kadowaki, T., Krone, W., Schroder, H., Bruning, J. C., Schubert, M. Neuronal IGF‐1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease. FASEB J . 23, 3315–3324 (2009). www.fasebj.org
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Similarly, knockout of Irs2 or the IGF-1 receptor can reduce cognitive impairment, neurodegeneration and premature mortality in mouse models of Alzheimer’s disease (71,72).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [71]
Citations
Cites
1 retracted
Puglielli, L., Ellis, B. C., Saunders, A. J., & Kovacs, D. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300466200 · Cited by 265
RetractedThe precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876
A C. elegans mutant that lives twice as long as wild type
Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993) · Nature · doi:10.1038/366461a0 · Cited by 3,387
Kimura, K. D., Tissenbaum, H. A., Liu, Y., & Ruvkun, G. (1997) · Science · doi:10.1126/science.277.5328.942 · Cited by 2,250
Role of Brain Insulin Receptor in Control of Body Weight and Reproduction
Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Müller-Wieland, D., & Kahn, C. R. (2000) · Science · doi:10.1126/science.289.5487.2122 · Cited by 2,235
Self-citationDiabetes mellitus and the risk of dementia: The Rotterdam Study
Ott, A., Stolk, R. P., van Harskamp, F., Pols, H. A. P., Hofman, A., & Breteler, M. M. B. (1999) · Neurology · doi:10.1212/wnl.53.9.1937 · Cited by 2,175
IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice
Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Géloën, A., Even, P. C., Cervera, P., & Le Bouc, Y. (2003) · Nature · doi:10.1038/nature01298 · Cited by 2,109
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
Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.
Lorenzo, A., & Yankner, B. A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.25.12243 · Cited by 1,324
Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., Jasionowski, M., Haass, C., & Fahrenholz, F. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.3922 · Cited by 975
El Khoury, J., Toft, M., Hickman, S. E., Means, T. K., Terada, K., Geula, C., & Luster, A. D. (2007) · Nature Medicine · doi:10.1038/nm1555 · Cited by 915
Opposing activities protect against age-onset proteotoxicity
Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W., & Dillin, A. (2006) · Science · doi:10.1126/science.1124646 · Cited by 843
Intranasal insulin improves cognition and modulates β-amyloid in early AD
Reger, M. A., Watson, G. S., Green, P. S., Wilkinson, C. W., Baker, L. D., Cholerton, B., Fishel, M. A., Plymate, S. R., Breitner, J. C. S., DeGroodt, W., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000265401.62434.36 · Cited by 830
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
Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease
Frölich, L., Blum-Degen, D., Bernstein, H.-G., Engelsberger, S., Humrich, J., Laufer, S., Muschner, D., Thalheimer, A., Türk, A., Hoyer, S., et al. (1998) · Journal of Neural Transmission · doi:10.1007/s007020050068 · Cited by 748
Leissring, M. A., Farris, W., Chang, A. Y., Walsh, D. M., Wu, X., Sun, X., Frosch, M. P., & Selkoe, D. J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00787-6 · Cited by 725
Rivera, E. J., Goldin, A., Fulmer, N., Tavares, R., Wands, J. R., & de la Monte, S. M. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-8304 · Cited by 723 · cited 2×
“Moreover, brain IGF-1 mRNA levels are diminished in late AD, whereas IGF-1 serum levels are increased in early stages of disease, suggesting that IGF-1 resistance plays a role in the pathogenesis of AD (14, 41).”
BackgroundHyperinsulinemia and risk of Alzheimer disease
Luchsinger, J. A., Tang, M.-X., Shea, S., & Mayeux, R. (2004) · Neurology · doi:10.1212/01.wnl.0000140292.04932.87 · Cited by 683
Regulation of C. elegans Life-Span by Insulinlike Signaling in the Nervous System
Wolkow, C. A., Kimura, K. D., Lee, M. S., & Ruvkun, G. (2000) · Science · doi:10.1126/science.290.5489.147 · Cited by 681
A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis
Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., et al. (2006) · Nature · doi:10.1038/nature05456 · Cited by 669
Type 2 diabetes mellitus, cognitive impairment and dementia
Stewart, R., & Liolitsa, D. (1999) · Diabetic Medicine · doi:10.1046/j.1464-5491.1999.00027.x · Cited by 562
Selman, C., Lingard, S., Choudhury, A. I., Batterham, R. L., Claret, M., Clements, M., Ramadani, F., Okkenhaug, K., Schuster, E., Blanc, E., et al. (2008) · The FASEB Journal · doi:10.1096/fj.07-9261com · Cited by 532
Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis
Taguchi, A., Wartschow, L. M., & White, M. F. (2007) · Science · doi:10.1126/science.1142179 · Cited by 523
Kubota, N., Tobe, K., Terauchi, Y., Eto, K., Yamauchi, T., Suzuki, R., Tsubamoto, Y., Komeda, K., Nakano, R., Miki, H., et al. (2000) · Diabetes · doi:10.2337/diabetes.49.11.1880 · Cited by 519
Self-citationInsulin receptors and insulin action in the brain: review and clinical implications
Schulingkamp, R. J., Pagano, T. C., Hung, D., & Raffa, R. B. (2000) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(00)00040-3 · Cited by 491
IRS-2 pathways integrate female reproduction and energy homeostasis
Burks, D. J., de Mora, J. F., Schubert, M., Withers, D. J., Myers, M. G., Towery, H. H., Altamuro, S. L., Flint, C. L., & White, M. F. (2000) · Nature · doi:10.1038/35030105 · Cited by 462
Self-citationCukierman‐Yaffe, T., Gerstein, H. C., Williamson, J. D., Lazar, R. M., Lovato, L., Miller, M. E., Coker, L. H., Murray, A. M., Sullivan, M. D., Marcovina, S. M., et al. (2009) · Diabetes Care · doi:10.2337/dc08-1153 · Cited by 462
Finch, C. E., & Ruvkun, G. (2001) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.2.1.435 · Cited by 446
Hill, J. M., Lesniak, M. A., Pert, C. B., & Roth, J. (1986) · Neuroscience · doi:10.1016/0306-4522(86)90082-5 · Cited by 413
Werther, G. A., Hogg, A., Oldfield, B. J., McKinley, M. J., Figdor, R., Allen, A. M., & Mendelsohn, F. A. O. (1987) · Endocrinology · doi:10.1210/endo-121-4-1562 · Cited by 333
Matsubara, E., Bryant‐Thomas, T., Pacheco Quinto, J., Henry, T. L., Poeggeler, B., Herbert, D., Cruz‐Sanchez, F., Chyan, Y., Smith, M. A., Perry, G., et al. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01654.x · Cited by 332
de la Monte, S. M., Tong, M., Lester-Coll, N. H., Plater, M. E., & Wands, J. R. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-10113 · Cited by 329
Zhao, L., Teter, B., Morihara, T., Lim, G. P., Ambegaokar, S. S., Ubeda, O. J., Frautschy, S. A., & Cole, G. M. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.2860-04.2004 · Cited by 329
The Emerging Genetic Architecture of Type 2 Diabetes
Doria, A., Patti, M., & Kahn, C. R. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.08.006 · Cited by 308
Rapid generation of inducible mouse mutants
Seibler, J. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng012 · Cited by 305
Brain IGF-1 Receptors Control Mammalian Growth and Lifespan through a Neuroendocrine Mechanism
Kappeler, L., Filho, C. D. D. M., Dupont, J., Leneuve, P., Cervera, P., Périn, L., Loudes, C., Blaise, A., Klein, R., Epelbaum, J., et al. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060254 · Cited by 305
McConlogue, L., Buttini, M., Anderson, J. P., Brigham, E. F., Chen, K. S., Freedman, S. B., Games, D., Johnson-Wood, K., Lee, M., Zeller, M., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611687200 · Cited by 300 · cited 1×
“In light of the recent notion that already marginal reductions of -secretase activity profoundly affect APP cleavage and disease progression (36), this mild reduction present in IRS-2-deficient mice may partially account for the observed delay in A accumulation in these animals, or another so far unknown mechanism may…”
BackgroundDistribution of insulin receptor-like immunoreactivity in the rat forebrain
Unger, J. W., McNeill, T. H., Moxley, R. T., White, M. F., Moss, A., & Livingston, J. N. (1989) · Neuroscience · doi:10.1016/0306-4522(89)90036-5 · Cited by 294
Stein, T. D., & Johnson, J. A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-17-07380.2002 · Cited by 290
Therapy insight, type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease
Haan, M. N. (2006) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0124 · Cited by 284
Impaired insulin secretion increases the risk of Alzheimer disease
Rönnemaa, E., Zethelius, B., Sundelöf, J. E., Sundström, J., Degerman-Gunnarsson, M., Berne, C., Lannfelt, L., & Kilander, L. (2008) · Neurology · doi:10.1212/01.wnl.0000310646.32212.3a · Cited by 240
Nathan, C., Calingasan, N., Nezezon, J., Ding, A., Lucia, M. S., La Perle, K., Fuortes, M., Lin, M., Ehrt, S., Kwon, N. S., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20051529 · Cited by 214
Insulin binds to brain blood vessels in vivo
van Houten, M., & Posner, B. I. (1979) · Nature · doi:10.1038/282623a0 · Cited by 180
Molecular connexions between dementia and diabetes
Cole, A. R., Astell, A. J., Green, C., & Sutherland, C. D. (2007) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2007.04.004 · Cited by 166
A Disturbance in the Neuronal Insulin Receptor Signal Transduction in Sporadic Alzheimer's Disease
Frölich, L., Blum-Degen, D., Riederer, P. F., & Hoyer, S. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07839.x · Cited by 160
Carlson, G. A., Borchelt, D. R., Dake, A., Turner, S., Danielson, V., Coffin, J. D., Eckman, C., Meiners, J., Nilsen, S. P., Younkin, S. G., et al. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.11.1951 · Cited by 158
Dementia: The leading predictor of death in a defined elderly population
Tschanz, J. T., Corcoran, C. M., Skoog, I. G., Khachaturian, A. S., Herrick, J. S., Hayden, K. M., Welsh-Bohmer, K. A., Calvert, T., Norton, M. C., Zandi, P. P., et al. (2004) · Neurology · doi:10.1212/01.wnl.0000118210.12660.c2 · Cited by 154
Meilandt, W. J., Cissé, M., Ho, K., Wu, T. Z., Esposito, L., Scearce-Levie, K. A., Cheng, I. H.-J., Yu, G.-Q., & Mucke, L. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2984-08.2009 · Cited by 144
Developmental regulation of energy metabolism in Caenorhabditis elegans
Wadsworth, W. G., & Riddle, D. L. (1989) · Developmental Biology · doi:10.1016/0012-1606(89)90214-5 · Cited by 140
An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β‐peptide generation
Costantini, C., Scrable, H. J., & Puglielli, L. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601062 · Cited by 134
Increased Circulating Insulin-like Growth Factor-1 in Late-onset Alzheimer's Disease
Vardy, E. R. L. C., Rice, P. J., Bowie, P. C. W., Holmes, J. D., Grant, P. J., & Hooper, N. M. (2007) · Journal of Alzheimer s Disease · doi:10.3233/jad-2007-12401 · Cited by 91
Adlerz, L., Holback, S., Multhaup, G., & Iverfeldt, K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611183200 · Cited by 82
Stachelscheid, H., Ibrahim, H., Koch, L., Schmitz, A., Tscharntke, M., Wunderlich, F. T., Scott, J. A., Michels, C., Wickenhauser, C., Haase, I., et al. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.141 · Cited by 70
Self-citationAlzheimer's disease could be “type 3 diabetes”
Pilcher, H. R. (2006) · The Lancet Neurology · doi:10.1016/s1474-4422(06)70434-3 · Cited by 63
Circumventricular Organs: Receptors and Mediators of Direct Peptide Hormone Action on Brain
van Houten, M., & Posner, B. I. (1983) · Advances in metabolic disorders · doi:10.1016/b978-0-12-027310-2.50015-3 · Cited by 61
Aging of the brain, neurotrophin signaling, and Alzheimer's disease: Is IGF1-R the common culprit?
Puglielli, L. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.01.010 · Cited by 61
Baskin, D. G., Davidson, D., Lewellen, T. K., & Graham, M. M. (1986) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(86)90044-0 · Cited by 51
Lovestone, S. (1999) · Neurology · doi:10.1212/wnl.53.9.1907 · Cited by 42
P1–182: Glycemic control and risk of dementia in a cohort of patients with type 2 diabetes
Whitmer, R. A., Selby, J. V., Eeden, S. K. V. D., Haan, M. N., Quesenberry, C. P., Minkoff, J. R., & Yaffe, K. S. (2006) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2006.05.557 · Cited by 1
Cited by
Sorted by citations
Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K. P., Stucky, A., Fuino, R. L., Kawaguchi, K. R., Samoyedny, A. J., Wilson, R. S., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59903 · Cited by 1,871
Neural mechanisms of ageing and cognitive decline
Bishop, N. A., Lu, T., & Yankner, B. A. (2010) · Nature · doi:10.1038/nature08983 · Cited by 1,323
The Amyloid Beta Peptide: A Chemist’s Perspective. Role in Alzheimer’s and Fibrillization
Hamley, I. W. (2012) · Chemical Reviews · doi:10.1021/cr3000994 · Cited by 892
Bomfim, T. R., Forny‐Germano, L., Sathler, L. B., Brito‐Moreira, J., Houzel, J., Decker, H., Silverman, M. A., Kazi, H., Melo, H. M., McClean, P. L., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci57256 · Cited by 849
Insulin Action in Brain Regulates Systemic Metabolism and Brain Function
Kleinridders, A., Ferris, H. A., Cai, W., & Kahn, C. R. (2014) · Diabetes · doi:10.2337/db14-0568 · Cited by 625
Metadata
- Authors
- Freude, S., Hettich, M. M., Schumann, C., Stöhr, O., Koch, L., Köhler, C., Udelhoven, M., Leeser, U., Müller, M., Kubota, N., Kadowaki, T., Krone, W., Schroder, H., Brüning, J. C., & Schubert, M.
- Affiliations
- University of Cologne (DE)
- The University of Tokyo (JP)
- Department II of Anatomy University of Cologne Cologne Germany
- Corresponding author
- Schubert, Markus
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2009-06
- Volume
- 23
- Issue
- 10
- Pages
- 3315-3324
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2134406000
- Cited by
- 218
- References
- 61
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 12 · 2023: 16 · 2022: 13 · 2021: 8 · 2020: 9 · 2019: 10 · 2018: 11 · 2017: 7 · 2016: 16 · 2015: 10 · 2014: 26 · 2013: 15 · 2012: 21
- FWCI
- 12.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Funders
- Fritz Thyssen Stiftung (AZ 10.06.2.209)
- Deutsche Forschungsgemeinschaft (Br-1492-7)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, IGF-1 resistance, IGF-1 receptor, insulin receptor substrate 2, insulin/IGF-1 signaling, amyloid-beta deposition, amyloid precursor protein, Tg2576 mice, premature mortality, hippocampus, APP processing, neuroprotection
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Female, Insulin-Like Growth Factor I, Male, Mice, Mutant Strains, Neurons, Amyloid beta-Peptides, Receptor, IGF Type 1, Mice, Insulin Receptor Substrate Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
