How does brain insulin resistance develop in Alzheimer's disease?

De Felice, Fernanda G.; Lourenco, Mychael V.; Ferreira, Sergio T.

doi:10.1016/j.jalz.2013.12.004

Cited by 337Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

How does brain insulin resistance develop in Alzheimer's disease?

De Felice, Fernanda G., Lourenco, Mychael V., Ferreira, Sergio T.·2014·Alzheimer's & Dementia

DOI 10.1016/j.jalz.2013.12.004

Open this paper in CoChat — free account

Abstract

Compelling preclinical and clinical evidence supports a pathophysiological connection between Alzheimer's disease (AD) and diabetes. Altered metabolism, inflammation, and insulin resistance are key pathological features of both diseases. For many years, it was generally considered that the brain was insensitive to insulin, but it is now accepted that this hormone has central neuromodulatory functions, including roles in learning and memory, that are impaired in AD. However, until recently, the molecular mechanisms accounting for brain insulin resistance in AD have remained elusive. Here, we review recent evidence that sheds light on how brain insulin dysfunction is initiated at a molecular level and why abnormal insulin signaling culminates in synaptic failure and memory decline. We also discuss the cellular basis underlying the beneficial effects of stimulation of brain insulin signaling on cognition. Discoveries summarized here provide pathophysiological background for identification of novel molecular targets and for development of alternative therapeutic approaches in AD.

Integrity signals

Registry

Crossref · 10.1016/j.jalz.2013.12.004

Cites

90 of 90 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

There is at some point a switch that triggers irreversible changes that lead toward amyloid beta toxicity and dementia.
“Yet, there is at some point, a “switch” that triggers irreversible changes that lead toward amyloid beta (Abeta) toxicity and dementia.”
From Neurobiological and Systemic Effects of Chronic Stress (2017) · cites this paper as [11]

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
Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397 · see citing works
Inflammatory Mechanisms in Obesity
Gregor, M. F., & Hotamisligil, G. S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101322 · Cited by 3,754 · see citing works
Diffusible, nonfibrillar ligands derived from Aβ <sub>1–42</sub> are potent central nervous system neurotoxins
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
A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359 · see citing works
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294 · see citing works
Diabetes 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 · see citing works
Alzheimer’s Dementia
Melnick, V. L., & Dubler, N. N. (1985) · Contemporary Issues in Biomedicine, Ethics, and Society · doi:10.1007/978-1-4612-5174-3 · Cited by 1,986 · see citing works
Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline
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 · see citing works
Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes?
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
Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway
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
Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial
Craft, S. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.233 · Cited by 1,253 · see citing works
Alzheimer’s disease is type 3 diabetes—Evidence reviewed
de la Monte, S. M., & Wands, J. R. (2008) · Journal of Diabetes Science and Technology · doi:10.1177/193229680800200619 · Cited by 1,158 · see citing works
Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss
Gong, Y., Chang, L., Viola, K. L., Lacor, P. N., Lambert, M. P., Finch, C. E., Krafft, G. A., & Klein, W. L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834302100 · Cited by 1,061 · see citing works
Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers
Lacor, P. N., Buniel, M. C., Chang, L., Fernandez, S. J., Gong, Y., Viola, K. L., Lambert, M. P., Velasco, P. T., Bigio, E. H., Finch, C. E., et al. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3432-04.2004 · Cited by 954 · see citing works
Signaling pathways in insulin action: molecular targets of insulin resistance
Pessin, J. E., & Saltiel, A. R. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10582 · Cited by 939 · see citing works
Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine
De Felice, F. G., Velasco, P. T., Lambert, M. P., Viola, K., Fernandez, S. J., Ferreira, S. T., & Klein, W. L. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m607483200 · Cited by 882 · see citing works
Self-citation
The many faces of insulin-like peptide signalling in the brain
Fernandez, A. M., & Torres-Alemán, I. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3209 · Cited by 872 · see citing works
Glucagon-like peptide-1 receptor is involved in learning and neuroprotection
During, M. J., Cao, L., Zuzga, D. S., Francis, J. S., Fitzsimons, H. L., Jiao, X., Bland, R. J., Klugmann, M., Banks, W. A., Drucker, D. J., et al. (2003) · Nature Medicine · doi:10.1038/nm919 · Cited by 851 · see citing works
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 · see citing works
An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers
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 830 · see citing works
Self-citation
Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling
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
Insulin signaling in health and disease
White, M. F. (2003) · Science · doi:10.1126/science.1092952 · Cited by 733 · cited 2× · see citing works
“Once phosphorylated at tyrosine residues, IRS proteins act as scaffolds that couple IR stimulation to downstream effectors, such as phosphoinositide 3-kinase (PI3K), murine thymoma viral oncogene homolog (or Akt)/protein kinase B, and mammalian target of rapamycin complex 1 [15], allowing metabolic and transcriptional…”
Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease
Hanson, L. R., & Frey, W. H. (2008) · BMC Neuroscience · doi:10.1186/1471-2202-9-s3-s5 · Cited by 700 · see citing works
Intranasal insulin improves memory in humans
Benedict, C., Hallschmid, M., Hatke, A., Schultes, B., Fehm, H. L., Born, J., & Kern, W. (2004) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2004.04.003 · Cited by 699 · see citing works
The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer's Disease
McClean, P. L., Parthsarathy, V., Faivre, E., & Hölscher, C. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0529-11.2011 · Cited by 698 · see citing works
Aβ Oligomers Cause Localized Ca <sup>2+</sup> Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2357-10.2010 · Cited by 686 · cited 2× · see citing works
“Another possibility is that excessive NMDAR activation and calcium influx triggered by oligomers [57,58,63,64] stimulate the activity of tyrosine phosphatases on IRS-1, as described for glutamate-induced neuronal damage [65], thus attenuating insulin signal transduction.”
Association of diabetes mellitus and dementia, the Rotterdam study
Ott, A., Stolk, R. P., Hofman, A., van Harskamp, F., Grobbee, D. E., & Breteler, M. M. B. (1996) · Diabetologia · doi:10.1007/s001250050588 · Cited by 677 · see citing works
Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers
De Felice, F. G., Vieira, M. N. N., Bomfim, T. R., Decker, H., Velasco, P. T., Lambert, M. P., Viola, K. L., Zhao, W.-Q., Ferreira, S. T., & Klein, W. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809158106 · Cited by 657 · cited 4× · see citing works
“Because AbOs trigger internalization and redistribution of neuronal IRs [49], it is possible that removal of IRs from the cell surface facilitates IRS-1pSer, a view that is consistent with our finding that insulin blocks both neuronal IR downregulation [50] and IRS-1pSer induced byAbOs [41].”
InfluentialSelf-citation
Insulin Resistance and Alzheimer-like Reductions in Regional Cerebral Glucose Metabolism for Cognitively Normal Adults With Prediabetes or Early Type 2 Diabetes
Baker, L. D., Cross, D. J., Minoshima, S., Belongia, D., Watson, G. S., & Craft, S. (2011) · Archives of Neurology · doi:10.1001/archneurol.2010.225 · Cited by 639 · see citing works
A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease
Davies, C. A., Mann, D. M. A., Sumpter, P. Q., & Yates, P. O. (1987) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(87)90057-8 · Cited by 628 · see citing works
The Unfolded Protein Response Is Activated in Pretangle Neurons in Alzheimer's Disease Hippocampus
Hoozemans, J. J. M., van Haastert, E. S., Nijholt, D. A. T., Rozemuller, A. J. M., Eikelenboom, P., & Scheper, W. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.080814 · Cited by 600 · see citing works
Amyloid beta oligomers induce impairment of neuronal insulin receptors
Zhao, W., De Felice, F. G., Fernandez, S., Chen, H., Lambert, M. P., Quon, M. J., Krafft, G. A., & Klein, W. L. (2008) · The FASEB Journal · doi:10.1096/fj.06-7703com · Cited by 587 · see citing works
-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin
Ma, Q.-L., Yang, F., Rosario, E. R., Ubeda, O. J., Beech, W., Gant, D. J., Chen, P. P., Hudspeth, B., Chen, C., Zhao, Y., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1071-09.2009 · Cited by 536 · see citing works
Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis
Hunter, K., & Hölscher, C. (2012) · BMC Neuroscience · doi:10.1186/1471-2202-13-33 · Cited by 504 · see citing works
Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses
Papadia, S., Soriano, F. X., Léveillé, F., Martel, M.-A., Dakin, K. A., Hansen, H. H., Kaindl, A., Sifringer, M., Fowler, J., Stefovska, V., et al. (2008) · Nature Neuroscience · doi:10.1038/nn2071 · Cited by 498 · see citing works
Double-Stranded RNA-Dependent Protein Kinase Links Pathogen Sensing with Stress and Metabolic Homeostasis
Nakamura, T., Furuhashi, M., Li, P., Cao, H., Tuncman, G., Sonenberg, N., Görgün, C. Z., & Hotamışlıgil, G. S. (2010) · Cell · doi:10.1016/j.cell.2010.01.001 · Cited by 498 · see citing works
Resolving controversies on the path to Alzheimer's therapeutics
Selkoe, D. J. (2011) · Nature Medicine · doi:10.1038/nm.2460 · Cited by 494 · see citing works
Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence
Freiherr, J., Hallschmid, M., Frey, W. H., Brünner, Y. F., Chapman, C. D., Hölscher, C., Craft, S., Felice, F. G. D., & Benedict, C. (2013) · CNS Drugs · doi:10.1007/s40263-013-0076-8 · Cited by 470 · see citing works
Different molecular cascades in different sites of the brain control memory consolidation
Izquierdo, I., Bevilaqua, L. R., Rossato, J. I., Bonini, J. S., Medina, J. H., & Cammarota, M. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.07.005 · Cited by 452 · see citing works
Insulin signaling meets mitochondria in metabolism
Cheng, Z., Tseng, Y. D., & White, M. F. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.06.005 · Cited by 449 · 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
GLP-1 receptor activation improves β cell function and survival following induction of endoplasmic reticulum stress
Yusta, B., Baggio, L. L., Estall, J. L., Koehler, J. A., Holland, D. P., Li, H., Pipeleers, D., Ling, Z., & Drucker, D. J. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.10.001 · Cited by 444 · see citing works
The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease
Ferreira, S. T., & Klein, W. L. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.003 · Cited by 442 · see citing works
Self-citation
Insulin resistance is associated with the pathology of Alzheimer disease: The Hisayama Study
Matsuzaki, T., Sasaki, K., Tanizaki, Y., Hata, J., Fujimi, K., Matsui, Y., Sekita, A., Suzuki, S. O., Kanba, S., Kiyohara, Y., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e3181eee25f · Cited by 432 · see citing works
Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects
Vilsbøll, T., Krarup, T., Madsbad, S., & Holst, J. J. (2003) · Regulatory Peptides · doi:10.1016/s0167-0115(03)00111-3 · Cited by 430 · see citing works
Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo
Chiu, S.-L., Chen, C.-M., & Cline, H. T. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.014 · Cited by 425 · see citing works
Preventing Alzheimer’s Disease
Selkoe, D. J. (2012) · Science · doi:10.1126/science.1228541 · Cited by 378 · see citing works
Diabetes mellitus and Alzheimer's disease: shared pathology and treatment?
Akter, K., Lanza, E. A., Martin, S. A., Myronyuk, N., Rua, M., & Raffa, R. B. (2011) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2010.03830.x · Cited by 352 · see citing works
Alzheimer’s disease and insulin resistance: translating basic science into clinical applications
Felice, F. G. D. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64595 · Cited by 328 · see citing works
Soluble Aβ Inhibits Specific Signal Transduction Cascades Common to the Insulin Receptor Pathway
Townsend, M., Mehta, T., & Selkoe, D. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610390200 · Cited by 318 · see citing works
Drug repositioning for Alzheimer's disease
Corbett, A., Pickett, J., Burns, A. S., Corcoran, J. P. T., Dunnett, S. B., Edison, P., Hagan, J. J., Holmes, C., Jones, E., Katona, C., et al. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3869 · Cited by 302 · see citing works
Insulin in the Brain: Sources, Localization and Functions
Ghasemi, R., Haeri, A., Dargahi, L., Mohamed, Z., & Ahmadiani, A. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8339-9 · Cited by 291 · see citing works
Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer's disease
Abbas, T. F., Faivre, É., & Hölscher, C. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.06.035 · Cited by 282 · see citing works
JNK3 Perpetuates Metabolic Stress Induced by Aβ Peptides
Yoon, S. O., Park, D. J., Ryu, J. C., Özer, H. G., Tep, C., Shin, Y. J., Lim, T. H., Pastorino, L., Kunwar, A. J., Walton, J. C., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.06.024 · Cited by 236 · see citing works
Brain insulin signaling: A key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes
McNay, E. C., & Recknagel, A. K. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.005 · Cited by 229 · see citing works
Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways
Lee, C.-C., Huang, C., & Hsu, K. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.06.003 · Cited by 227 · see citing works
A Specific Enzyme-Linked Immunosorbent Assay for Measuring β-Amyloid Protein Oligomers in Human Plasma and Brain Tissue of Patients With Alzheimer Disease
Xia, W., Yang, T., Shankar, G. M., Smith, I. M., Shen, Y., Walsh, D. M., & Selkoe, D. J. (2009) · Archives of Neurology · doi:10.1001/archneurol.2008.565 · Cited by 215 · see citing works
The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer’s Disease
Cole, G. M., & Frautschy, S. A. (2006) · Experimental Gerontology · doi:10.1016/j.exger.2006.08.009 · Cited by 189 · see citing works
Immunoelectron microscopic study of synaptic pathology in Alzheimer's disease
Masliah, E., Hansen, L. A., Albright, T., Mallory, M. E., & Terry, R. D. (1991) · Acta Neuropathologica · doi:10.1007/bf00293464 · Cited by 174 · see citing works
Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions
Schiöth, H. B., Craft, S., Brooks, S. J., Frey, W. H., & Benedict, C. (2011) · Molecular Neurobiology · doi:10.1007/s12035-011-8229-6 · Cited by 168 · see citing works
N ‐Methyl‐ d ‐aspartate receptors are required for synaptic targeting of Alzheimer’s toxic amyloid‐β peptide oligomers
Decker, H., Jürgensen, S., Adrover, M. F., Brito‐Moreira, J., Bomfim, T. R., Klein, W. L., Epstein, A. L., Felice, F. G. D., Jerusalinsky, D. A., & Ferreira, S. T. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07058.x · Cited by 164 · see citing works
Self-citation
Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model
Wang, X., Zheng, W. H., Xie, J., Wang, T., Wang, S., Teng, W., & Wang, Z. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-46 · Cited by 161 · see citing works
Aβ Oligomer-Induced Synapse Degeneration in Alzheimer’s Disease
Wilcox, K. C., Lacor, P. N., Pitt, J. E., & Klein, W. L. (2011) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-011-9691-4 · Cited by 156 · see citing works
Amyloid-β oligomers link depressive-like behavior and cognitive deficits in mice
Ledo, J. H., Azevedo, E. P., Clarke, J. R., Ribeiro, F. C., Figueiredo, C. P., Foguel, D., Felice, F. G. D., & Ferreira, S. T. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.168 · Cited by 156 · see citing works
Self-citation
Type 2 Diabetes Mellitus and Cognitive Decline in Two Large Cohorts of Community‐Dwelling Older Adults
Okereke, O. I., Kang, J. H., Cook, N. R., Gaziano, J. M., Manson, J. E., Buring, J. E., & Grodstein, F. (2008) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2008.01686.x · Cited by 155 · see citing works
Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ
Zhao, W.-Q., Lacor, P. N., Chen, H., Lambert, M. P., Quon, M. J., Krafft, G. A., & Klein, W. L. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.011015 · Cited by 154 · see citing works
Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress
Manolopoulos, K. N., Klotz, L.-O., Korsten, P., Bornstein, S. R., & Barthel, A. (2010) · Molecular Psychiatry · doi:10.1038/mp.2010.17 · Cited by 150 · see citing works
Liraglutide protects against amyloid-β protein-induced impairment of spatial learning and memory in rats
Han, W.-N., Hölscher, C., Yuan, L., Yang, W., Wang, X., Wu, M., & Qi, J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.04.009 · Cited by 138 · see citing works
Amyloid β-Peptide Oligomers Stimulate RyR-Mediated Ca 2+ Release Inducing Mitochondrial Fragmentation in Hippocampal Neurons and Prevent RyR-Mediated Dendritic Spine Remodeling Produced by BDNF
Paula-Lima, A. C., Adasme, T., SanMartín, C. D., Sebollela, A. S., Hetz, C. A., Carrasco, M. A., Ferreira, S. T., & Hidalgo, C. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3287 · Cited by 136 · see citing works
Self-citation
Insulin receptor substrate proteins and diabetes
Lee, Y. H., & White, M. F. (2004) · Archives of Pharmacal Research · doi:10.1007/bf02980074 · Cited by 135 · see citing works
Feed-forward signaling of TNF-α and NF-κB via IKK-β pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice
Yang, J., Park, Y., Zhang, H., Xu, X., Laine, G. A., Dellsperger, K. C., & Zhang, C. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01199.2008 · Cited by 114 · see citing works
Insulin resistance and AD—extending the translational path
Craft, S. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.112 · Cited by 113 · see citing works
ADDLs and the signaling web that leads to Alzheimer’s disease
Krafft, G. A., & Klein, W. L. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.07.012 · Cited by 111 · see citing works
Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats.
Hajali, V., Mohaddes, G., & Babri, S. (2009) · Behavioral Neuroscience · doi:10.1037/a0017722 · Cited by 97 · see citing works
Aβ Oligomers Induce Glutamate Release from Hippocampal Neurons
Brito‐Moreira, J., Paula-Lima, A. C., Bomfim, T. R., de Oliveira, F. F., Sepúlveda, F. J., Mello, F. G. D., Aguayo, L. G., Panizzutti, R., & Ferreira, S. T. (2011) · Current Alzheimer Research · doi:10.2174/156720511796391917 · Cited by 95 · see citing works
Self-citation
Insulin Promotes Neuronal Survival via the Alternatively Spliced Protein Kinase CδII Isoform
Apostolatos, A. H., Song, S., Acosta, S., Peart, M. S., Watson, J. E., Bickford, P. C., Cooper, D. R., & Patel, N. A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.313080 · Cited by 94 · see citing works
Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site: FOXO1 is a FOXO target gene
Mubarak, B. R. A., Soriano, F. X., & Hardingham, G. E. (2009) · Channels · doi:10.4161/chan.3.4.9381 · Cited by 82 · see citing works
Insulin rescues amyloid β-induced impairment of hippocampal long-term potentiation
Lee, C.-C., Kuo, Y.-M., Huang, C.-C., & Hsu, K.-S. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.06.014 · Cited by 81 · see citing works
Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer´s disease - protocol for a controlled, randomized double-blinded trial.
Egefjord, L., Gejl, M., Møller, A., Brændgaard, H., Gottrup, H., Antropova, O., Møller, N., Poulsen, H. E., GJEDDE, A. H., Brock, B., et al. (2012) · PubMed · Cited by 80 · see citing works
Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway
Son, S., Song, H., Byun, J., Park, K., Jang, H., Park, Y., & Mook-Jung, I. (2012) · Diabetes · doi:10.2337/db11-1735 · Cited by 74 · see citing works
Brain Glucose Metabolism Is Controlled by Amplification and Desensitization of the Neuronal Insulin Receptora
Hoyer, S., Henneberg, N., KNAPP, S., Lannert, H., & MARTIN, E. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb34448.x · Cited by 73 · see citing works
Glutamate Acting on N-Methyl-d-aspartate Receptors Attenuates Insulin-like Growth Factor-1 Receptor Tyrosine Phosphorylation and Its Survival Signaling Properties in Rat Hippocampal Neurons
Zheng, W., & Quirion, R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807914200 · Cited by 56 · see citing works
Diabetes type II: A risk factor for depression-Parkinson–Alzheimer?
Riederer, P., Bartl, J., Laux, G., & Grünblatt, E. (2011) · Neurotoxicity Research · doi:10.1007/s12640-010-9203-1 · Cited by 51 · see citing works
Brain insulin resistance accelerates Aβ fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes
Yamamoto, N., Matsubara, T., Sobue, K., Tanida, M., Kasahara, R., Naruse, K., Taniura, H., Sato, T., & Suzuki, K. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07668.x · Cited by 48 · see citing works
Amyloid load and neural elements in Alzheimer's disease and nondemented individuals with high amyloid plaque density
Mochizuki, A., Peterson, J. W., Mufson, E. J., & Trapp, B. D. (1996) · Experimental Neurology · doi:10.1006/exnr.1996.0181 · Cited by 43 · see citing works
Alzheimer’s disease beyond APOE
van Es, M. A., & van den Berg, L. H. (2009) · Nature Genetics · doi:10.1038/ng1009-1047 · Cited by 43 · see citing works
US government sets out Alzheimer’s plan
Wadman, M. (2012) · Nature · doi:10.1038/485426a · Cited by 33 · see citing works
Permissive Role of Insulin in the Expression of Long-Term Potentiation in the Hippocampus of Immature Rats
Zhao, W., Wu, X., Xie, H., Ke, Y., & Yung, W. (2010) · Neurosignals · doi:10.1159/000324040 · Cited by 27 · see citing works
Targeting Alzheimer's Pathology through PPARγ Signaling: Modulation of Microglial Function
Lourenco, M. V., & Ledo, J. H. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0172-13.2013 · Cited by 22 · see citing works
Self-citation

Flagged first, then by citations

Sorted by citations

Neurobiological and Systemic Effects of Chronic Stress
McEwen, B. S. (2017) · Chronic Stress · doi:10.1177/2470547017692328 · Cited by 1,059 · see citing works
“Yet, there is at some point, a ‘‘switch’’ that triggers irreversible changes that lead toward amyloid beta (Abeta) toxicity and dementia.(11) Before this switch is triggered, synaptic NMDA receptor activation normally has an antioxidant role by suppressing FOXO1 transcription factor in hippocampus, but abnormal and ex…”
BackgroundInfluential
Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models
Lourenco, M. V., Frozza, R. L., de Freitas, G. B., Zhang, H., Kincheski, G. C., Ribeiro, F. C., Gonçalves, R. A., Clarke, J. R., Beckman, D., Staniszewski, A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0275-4 · Cited by 935 · see citing works
Self-citation
Trends in insulin resistance: insights into mechanisms and therapeutic strategy
Li, M., Chi, X., Wang, Y., Setrerrahmane, S., Xie, W., & Xu, H. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01073-0 · Cited by 939 · see citing works
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870 · see citing works
Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis
Viola, K. L., & Klein, W. L. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1386-3 · Cited by 628 · see citing works
Melatonin and inflammation-Story of a double-edged blade
Hardeland, R. (2018) · Journal of Pineal Research · doi:10.1111/jpi.12525 · Cited by 455 · see citing works
The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action
Athauda, D., & Foltynie, T. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.01.013 · Cited by 383 · see citing works
Alzheimer's disease and type 2 diabetes: a critical assessment of the shared pathological traits
Chatterjee, S., & Mudher, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00383 · Cited by 270 · see citing works
Heterogeneity in Alzheimer’s Disease Diagnosis and Progression Rates: Implications for Therapeutic Trials
Duara, R., & Barker, W. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01185-z · Cited by 187 · see citing works
Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases
Diz-Chaves, Y., Mastoor, Z., Spuch, C., González-Matías, L. C., & Mallo, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179583 · Cited by 148 · see citing works
Diet-Derived Fatty Acids, Brain Inflammation, and Mental Health
Melo, H. M., Santos, L. E., & Ferreira, S. T. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00265 · Cited by 136 · see citing works
Self-citation
Redefining neuroendocrinology: Epigenetics of brain-body communication over the life course
McEwen, B. S. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.11.001 · Cited by 129 · see citing works
Protective actions of exercise-related FNDC5/irisin in memory and Alzheimer's disease
de Freitas, G. B., Lourenco, M. V., & De Felice, F. G. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15039 · Cited by 120 · see citing works
Self-citation
Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: A new paradigm
Barone, E., Di Domenico, F., Cassano, T., Arena, A., Tramutola, A., Lavecchia, M. A., Coccia, R., Butterfield, D. A., & Perluigi, M. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.12.012 · Cited by 100 · see citing works
Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease
Mroczko, B., Groblewska, M., Litman-Zawadzka, A., Kornhuber, J., & Lewczuk, P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071884 · Cited by 97 · see citing works
Novel GLP-1 (Glucagon-Like Peptide-1) Analogues and Insulin in the Treatment for Alzheimer’s Disease and Other Neurodegenerative Diseases
Calsolaro, V., & Edison, P. (2015) · CNS Drugs · doi:10.1007/s40263-015-0301-8 · Cited by 93 · see citing works
Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance
Bigio, B., Mathé, A. A., Sousa, V. C., Zelli, D., Svenningsson, P., McEwen, B. S., & Nasca, C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603111113 · Cited by 85 · see citing works
mTOR and neuronal cell cycle reentry: how impaired brain insulin signaling promotes Alzheimer's disease
Norambuena, A., Wallrabe, H., McMahon, L., Silva, A., Swanson, E., Khan, S. S., Baerthlein, D., Kodis, E., Oddo, S., Mandell, J. W., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.08.015 · Cited by 79 · see citing works
A review of the mechanisms underlying selected comorbidities in Alzheimer’s disease
Maciejewska, K., Czarnecka, K., & Szymański, P. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00293-5 · Cited by 64 · see citing works
Brain insulin, insulin‐like growth factor 1 and glucagon‐like peptide 1 signalling in Alzheimer’s disease
Ferreira, S. T. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12959 · Cited by 59 · see citing works
Self-citation
Challenges of Repurposing Tetracyclines for the Treatment of Alzheimer’s and Parkinson’s Disease
Markulin, I., Matasin, M., Turk, V. E., & Salković-Petrisic, M. (2022) · Journal of Neural Transmission · doi:10.1007/s00702-021-02457-2 · Cited by 36 · see citing works
Impact of ectopic fat on brain structure and cognitive function: A systematic review and meta-analysis from observational studies
Song, Z.-H., Liu, J., Wang, X.-F., Simó, R., Zhang, C., & Zhou, J.-B. (2023) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2023.101082 · Cited by 14 · see citing works
FAK-mediated signaling controls amyloid beta overload, learning and memory deficits in a mouse model of Alzheimer’s disease
Saleh, B., Srikanth, K. D., Sneh, T., Yue, L., Pelech, S., Elliott, E., & Gil-Henn, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169055 · Cited by 10 · see citing works

On the Theory of Social Mechanism
Cui-ping, K. (2007) · Journal of Nanyang Normal University
A Study on Mechanism of Synergic Development of the Regional High -tech In dustries between Mainland and Taiwan
Zhu, B. (2002) · Zhongguo ruankexue
Saturated fatty acids-induced miR-424–5p aggravates insulin resistance via targeting insulin receptor in hepatocytes
Min, K.-H., Yang, W., & Lee, W. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.07.084 · Cited by 45 · see citing works
Characteristics of Insulin Receptors and Insulin Action in Human Myelogenous Leukemia Cell Line K-562
Yamanouchi, T., Tsushima, T., Akanuma, Y., et al. (1985) · Diabetes · doi:10.2337/diab.34.4.347 · Cited by 7 · see citing works
Acute effects of insulin on surface insulin receptors in isolated hepatocytes. Evidence for a recycling pathway
Bonser, A. M., & Garcia‐Webb, P. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80308-3 · Cited by 9 · see citing works

Authors: De Felice, F. G., Lourenco, M. V., & Ferreira, S. T.
Affiliations: Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro Rio de Janeiro Brazil
Universidade Federal do Rio de Janeiro (BR)
ORCID: Lourenco, Mychael V.
Ferreira, Sergio T.
Venue: Alzheimer's & Dementia
Publisher: Wiley
Published: 2014-02
Volume: 10
Issue: 1S
Pages: S26-32
ISSN: 1552-5260 (ISSN-L)
1552-5279
DOI: 10.1016/j.jalz.2013.12.004
OpenAlex: W2061313710
Cited by: 337
References: 90
Citations by year: 2026: 12 · 2025: 16 · 2024: 21 · 2023: 27 · 2022: 23 · 2021: 31 · 2020: 35 · 2019: 30 · 2018: 45 · 2017: 34 · 2016: 28 · 2015: 24 · 2014: 10
FWCI: 3.74
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Alzheimer s & Dementia (publishedVersion)
PubMed (publishedVersion)
Funders: Conselho Nacional de Desenvolvimento Científico e Tecnológico
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
Topics: Health Sciences › Medicine › Physiology › 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, brain insulin resistance
MeSH terms: Alzheimer Disease, Animals, Brain, Humans, Insulin Resistance, Metabolic Diseases

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

How does brain insulin resistance develop in Alzheimer's disease?

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks