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Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers
Open accessAbstract
Synapse deterioration underlying severe memory loss in early Alzheimer's disease (AD) is thought to be caused by soluble amyloid beta (Aβ) oligomers. Mechanistically, soluble Aβ oligomers, also referred to as Aβ-derived diffusible ligands (ADDLs), act as highly specific pathogenic ligands, binding to sites localized at particular synapses. This binding triggers oxidative stress, loss of synaptic spines, and ectopic redistribution of receptors critical to plasticity and memory. We report here the existence of a protective mechanism that naturally shields synapses against ADDL-induced deterioration. Synapse pathology was investigated in mature cultures of hippocampal neurons. Before spine loss, ADDLs caused major downregulation of plasma membrane insulin receptors (IRs), via a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition. Most significantly, this loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration, could be completely prevented by insulin. At submaximal insulin doses, protection was potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes. The mechanism of insulin protection entailed a marked reduction in pathogenic ADDL binding. Surprisingly, insulin failed to block ADDL binding when IR tyrosine kinase activity was inhibited; in fact, a significant increase in binding was caused by IR inhibition. The protective role of insulin thus derives from IR signaling-dependent downregulation of ADDL binding sites rather than ligand competition. The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.
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TL;DR
In mature hippocampal cultures, insulin signaling prevented Aβ oligomer (ADDL) binding, oxidative stress, insulin receptor loss, and spine degeneration, with protection requiring insulin receptor tyrosine kinase activity rather than simple ligand competition. Rosiglitazone potentiated submaximal insulin’s protection, suggesting that enhancing CNS insulin signaling may defend synapses against Alzheimer’s-linked toxins.
Key findings
- ADDLs caused loss of surface insulin receptors (IRs): surface-exposed IR levels decreased by 22% after 30 min and 68% after 3 h of exposure to 100 nM ADDLs.
- The CK2 inhibitor DMAT completely blocked ADDL-induced loss of both IRs and NMDA receptors; the CaMKII inhibitor KN93 afforded partial protection.
- Insulin at 100 nM partially prevented and 1 μM completely blocked ADDL-induced dendritic IR loss; 1 μM insulin caused a major (≈70%) blockade of ADDL binding, and 100 nM insulin + 10 μM rosiglitazone produced IR levels similar to control or 1 μM insulin.
- Insulin prevented ADDL-induced oxidative stress and 24-h spine degeneration; protection required IR activity, because AG1024 (5 μM) abolished insulin’s ability to block ADDL binding and increased binding when added alone or with insulin.
Methods
- Primary mature hippocampal neuronal cultures were used after 21 DIV and treated at 37 °C for 3 h with 100 nM ADDLs or vehicle; insulin (100 nM or 1 μM) or rosiglitazone (10 μM) was added 30 min before ADDLs, and AG1024 (5 μM) was added 30 min before insulin.
- ADDLs were prepared from Aβ1–42; outcomes were assessed by surface biotinylation/Western blot, immunocytochemistry with IRα and NU4 anti-ADDL antibodies, phalloidin labeling of spines, and dihydroethidium (DHE) for reactive oxygen species.
- Immunofluorescence intensities were analyzed with NIH ImageJ.
Limitations
- The paper states that the nature of the ADDL binding sites “has yet to be determined” and that future identification of proteins lost from the membrane in response to insulin could provide insight into them.
- Evident from the text: all experiments were performed in mature hippocampal neuronal cultures; no in vivo or human data are reported in this study.
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20 Own interpretation · 2 Own result · 1 Not checked yet · 1 No basis given
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In the paper
“we found that DMAT, a CK2 inhibitor, completely blocked ADDL-induced loss of both IRs and NMDARs from the dendrites of hippocampal neurons”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Results > Casein Kinase 2 (CK2) and Ca2+/Calmodulin-Dependent Kinase II (CaMKII) Mediate ADDL-Induced Loss of IRs and NMDA subtype glutamate receptors (NMDARs).
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In the paper
“These results are consistent with the notion that ADDLs have a selective impact in accelerating the endocytosis of particular surface proteins, such as IRs.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Results > ADDLs Induce Loss of IRs from Neuronal Surfaces.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Decreased binding is the result of downregulation of ADDL binding sites through a mechanism requiring insulin receptor (IR) tyrosine kinase activity.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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“Results here support the hypothesis that the beneficial effect of insulin in AD derives at least in part from an acute decrease in ADDL synaptotoxicity.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“A plausible mechanism of protection is provided by the current finding that rosiglitazone potentiates the ability of insulin to protect synapses against ADDLs.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, ADDL-induced loss of IRs might represent an important early mechanism underlying memory impairment and other pathological features of AD.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Results > Casein Kinase 2 (CK2) and Ca2+/Calmodulin-Dependent Kinase II (CaMKII) Mediate ADDL-Induced Loss of IRs and NMDA subtype glutamate receptors (NMDARs).
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Given that insulin protects neurons against AD-causing neurotoxins, it follows that dysfunctional CNS insulin signaling would be an AD risk factor.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“indicating potentiation of insulin protection by rosiglitazone.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Results > Rosiglitazone Potentiates the Neuroprotective Action of Insulin.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Results strongly support the hypothesis that insulin signaling plays a role in defending CNS neurons against AD and provide a disease-specific basis for treatments based on stimulating CNS insulin pathways.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In fact, AG1024 caused significant increases in neuronal ADDL binding both when AG1024 was added alone and in the presence of exogenous insulin.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Results > Protection by Insulin Requires IR Activity.
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In the paper
“We have identified a unique molecular mechanism that protects CNS neurons against ADDLs, soluble neurotoxins putatively responsible for the synaptic deterioration underlying Alzheimer's memory failure.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, physiological insulin and pathological ADDLs negatively regulate the abundance of each other's binding sites, creating a competitive balance between synapse survival and degeneration.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus the mechanism of protection does not involve simple competition between ADDLs and insulin for a common binding site on the neuronal surface, but rather is a signaling-dependent downregulation of ADDL binding sites.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Results show that insulin blocks ADDL binding to synapses, thereby preventing the ensuing neurotoxicity.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This indicates that loss of insulin receptors precedes and is not a consequence of overall collapse and retraction of synaptic spines.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Results > Insulin Prevents ADDL-Induced Synapse Loss.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“An elevated risk for AD also exists in type 2 diabetes patients, who manifest deficient CNS insulin signaling.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Discussion
What the sources say
- Not checked yetcites [31] Craft S. Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res. 2007;4:147–152. doi: 10.2174/156720507780362137. [[DOI](https://doi.org/10.2174/156720507780362137)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/17430239/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Curr%20Alzheimer%20Res&title=Insulin%20resistance%20and%20Alzheimer's%20disease%20pathogenesis:%20potential%20mechanisms%20and%20implications%20for%20treatment&author=S%20Craft&volume=4&publication_year=2007&pages=147-152&pmid=17430239&do source
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In the paper
“Insulin signaling downregulates ADDL binding, while ADDLs downregulate IRs.”
§ Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Internalization occurs by a mechanism mediated by casein kinase 2 (CK2) and Ca2+/calmodulin-dependent kinase 2 (CaMK II), which also are involved in ADDL-induced internalization of NMDA receptors (De Felice et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2009
In the citing paper
“Aβ oligomers induce a striking redistribution of IRs, causing their internalization from dendritic membranes and accumulation in the cell body. This renders neurons insulin resistant (De Felice et al., 2009; De Felice et al., 2008; Zhao et al., 2008).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2009
In the citing paper
“insulin itself blocks the pathological binding of Aβ oligomers and the resulting redistribution of IRs and synapse loss (De Felice et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2009
In the citing paper
“Clustering of oligomers at synapses, moreover, shows a cause-and-effect relationship with characteristic Alzheimer neuropathologies. AD type tau hyperphosphorylation (De Felice et al., 2008), redistribution of insulin receptors (De Felice et al., 2009; Zhao et al., 2008), spine loss (Lacor et al., 2007) and oxidative stress (De Felice et al., 2007; Decker et al., 2010a) are manifest exclusively in”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2009
In the citing paper
“pharmacological experiments indicate involvement of CaMKII and casein kinase II (De Felice et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as De Felice et al., 2009
In the citing paper
“Several neuronal receptors have been proposed as mediating the effect of Aβ on synaptic plasticity and memory, including the α-7-nicotinic (16), glutamatergic (39–40), and insulin (14) receptors.”
From Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein (2010) · cites this paper as [14]
In the citing paper
“deteriorations in the clearance and degradation of Aβ as a result of impaired insulin signalling are discussed as a mechanism that increases the risk of AD 135 and may be improved by insulin administration.136,137”
From Intranasal insulin (2021) · cites this paper as [136]
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RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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“Calcium-dependent activation of calcium/calmodulin-dependent kinase II (CaMKII) and casein kinase II (CKII) also appears to mediate removal of NMDARs from synapses (De Felice et al., 2009; not represented in the current scheme).”
BackgroundInfluentialSelf-citationHsu, C.-C., Wahlqvist, M. L., Lee, M.-S., & Tsai, H.-N. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101524 · Cited by 372
McClean, P. L., & Hölscher, C. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.08.005 · Cited by 362
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Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease
Ferreira, S. T., Clarke, J. R., Bomfim, T. R., & Felice, F. G. D. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.12.010 · Cited by 363
“[33] De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, et al.”
Self-citationKim, B., & Feldman, E. L. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2015.3 · Cited by 372
Silva, N. M. L. E., Gonçalves, R. A., Pascoal, T. A., Lima‐Filho, R. A. S., Resende, E. D. P. F., Vieira, É. L. M., Teixeira, A. L., de Souza, L. C., Peny, J. A., Fortuna, J. T. S., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01349-z · Cited by 364
Self-citationTramutola, A., Triplett, J. C., Di Domenico, F., Niedowicz, D. M., Murphy, M. P., Coccia, R., Perluigi, M., & Butterfield, D. A. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13037 · Cited by 347
Perluigi, M., Di Domenico, F., & Butterfield, D. A. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.03.014 · Cited by 339
“Aβ monomers and soluble oligomers bind to IRs, can induce IR internalization in neurons and remove IR from dendrites, imitating what is seen in AD brain (De Felice et al., 2009; Moloney et al., 2010; Zhao et al., 2008, 2009).”
How does brain insulin resistance develop in Alzheimer's disease?
De Felice, F. G., Lourenco, M. V., & Ferreira, S. T. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.12.004 · Cited by 337
“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-citationCraft, S., Claxton, A., Baker, L. D., Hanson, A. J., Cholerton, B., Trittschuh, E. H., Dahl, D., Caulder, E., Neth, B., Montine, T. J., et al. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-161256 · Cited by 335
“phorylation in preclinical models [4].”
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 336
“Indeed, insulin may have important therapeutic implications in early and/or intermediate phases of AD (20, 119), preventing oligomer binding and blocking the pathology of IRs in cultured neurons (15, 16) and in AD brains (46).”
InfluentialSelf-citationAltered Expression of Diabetes-Related Genes in Alzheimer's Disease Brains: The Hisayama Study
Hokama, M., Oka, S., Leon, J., Ninomiya, T., Honda, H., Sasaki, K., Iwaki, T., Ohara, T., Sasaki, T., LaFerla, F. M., et al. (2013) · Cerebral Cortex · doi:10.1093/cercor/bht101 · Cited by 323
“It has also been shown that insulin prevents the loss of surface insulin receptors, oxidative stress, and synaptic spine loss in cultured mature hippocampal neurons caused by Aβ-derived diffusible ligands (De Felice et al. 2009).”
BackgroundSynaptic changes in Alzheimer’s disease and its models
Pozueta, J., Lefort, R., & Shelanski, M. L. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.05.050 · Cited by 319
Oxidative stress, protein modification and Alzheimer disease
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The Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 316
Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives
Béard, E., Lengacher, S., Dias, S., Magistretti, P. J., & Finsterwald, C. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2021.825816 · Cited by 326
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The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer’s Disease
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Self-citationAberrant insulin signaling in Alzheimer's disease: current knowledge
Bedse, G., Domenico, F. D., Serviddio, G., & Cassano, T. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00204 · Cited by 313
“IR down-regulation and synaptic loss are markedly decreased by insulin treatment (de Felice et al., 2009).”
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Chen, X., & Mobley, W. C. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00659 · Cited by 302
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Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer's disease
Akhtar, A., & Sah, S. P. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104707 · Cited by 297
Insulin Resistance and Alzheimer’s Disease: Bioenergetic Linkages
Neth, B. J., & Craft, S. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00345 · Cited by 284
“Insulin has been shown to prevent binding of Aβ to synapses, thus minimizing synaptic damage (De Felice et al., 2009).”
BackgroundThe role of type 2 diabetes in neurodegeneration
Verdile, G., Fuller, S. J., & Martins, R. N. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.04.008 · Cited by 290
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
“Conversely, treating AD patients and transgenic animals with intranasal insulin lowers the concentration of soluble Aβ and improves memory (De Felice et al., 2009).”
BackgroundRole of the Blood-Brain Barrier in Central Nervous System Insulin Resistance
Rhea, E. M., & Banks, W. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00521 · Cited by 272
“In addition, Aβ oligomers have been shown to lead to the removal of insulin receptors from the membranes of neuronal processes (Zhao et al., 2008; De Felice et al., 2009).”
BackgroundMa, T., Hoeffer, C. A., Capetillo-Zarate, E., Yu, F., Wong, H., Lin, M. T., Tampellini, D., Klann, E., Blitzer, R. D., & Gouras, G. K. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012845 · Cited by 262
“On one hand, Ab was shown to impair insulin-PI3K-AKT signaling [2,45–47] and insulin treatment was reported to improve cognitive function in patients with early AD [48], while on the other hand, AD transgenic mice with reduced insulin signaling were reported to be protected against cognitive decline [49].”
BackgroundThe brain as an insulin-sensitive metabolic organ
Milstein, J. L., & Ferris, H. A. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101234 · Cited by 274
Diabetes and Cardiovascular Disease in Older Adults: Current Status and Future Directions
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Amyloid-β Receptors: The Good, the Bad, and the Prion Protein
Jarosz-Griffiths, H. H., Noble, E., Rushworth, J. V., & Hooper, N. M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.702704 · Cited by 256
Reich, N., & Hölscher, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.970925 · Cited by 248
Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes
Dutta, S., Shah, R., Singhal, S., Dutta, S. B., Bansal, S., Sinha, S., & Haque, M. (2023) · Drug Design Development and Therapy · doi:10.2147/dddt.s409373 · Cited by 296
Amyloid-β as a Modulator of Synaptic Plasticity
Parihar, M. S., & Brewer, G. J. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101020 · Cited by 264
“of AMPA and NMDA receptors at the neuronal plasma membrane [74,75,218,219].”
Batista, A. F., Forny‐Germano, L., Clarke, J. R., Silva, N. M. L. E., Brito‐Moreira, J., Boehnke, S. E., Winterborn, A., Coe, B. C., Lablans, A., Vital, J. F. S., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5056 · Cited by 251
Self-citationPrion protein and Aβ‐related synaptic toxicity impairment
Calella, A. M., Farinelli, M., Nuvolone, M., Mirante, O., Moos, R., Falsig, J., Mansuy, I. M., & Aguzzi, A. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000082 · Cited by 242
“Several membrane proteins have been reported to bind soluble Ab oligomers—thereby candidat- ing as potential transducers of toxicity (Deane et al, 2004; De Felice et al, 2009; Shankar et al, 2007; Snyder et al, 2005; Yan et al, 1996).”
Vandal, M., White, P. J., Tremblay, C., St‐Amour, I., Chevrier, G., Émond, V., Lefrançois, D., Virgili, J., Planel, E., Giguère, Y., et al. (2014) · Diabetes · doi:10.2337/db14-0375 · Cited by 243
McNay, E. C., & Recknagel, A. K. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.005 · Cited by 233
“…Ab (Gasparini, Netzer, Greengard, & Xu, 2002; Gasparini et al., 2001; Wei Qiao & Marshal, 2006) and may directly prevent pathogenic Ab binding (De Felice et al., 2009) as well as being able to reverse cognitive deficits and reduce amyloid load in AD patients (Reger et al., 2006b; Reger, Watson,…”
Insulin, cognition, and dementia
Cholerton, B., Baker, L. D., & Craft, S. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.08.008 · Cited by 243
“This process was also prevented by pretreatment with insulin (De Felice et al., 2009).”
BackgroundInsulin Resistance in Alzheimer's Disease
Ferreira, L. S. S., Fernandes, C., Vieira, M. N. N., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00830 · Cited by 238
“We identified that insulin prevents Aβ oligomers-induced synapse loss and surface IR reduction in vitro (De Felice et al., 2009) and also rescued the PKRmediated endoplasmic reticulum stress in AD models (Lourenco et al., 2013).”
BackgroundSelf-citationInsulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: Targets for disease modification?
Bassil, F., Fernagut, P., Bézard, E., & Meissner, W. G. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2014.02.005 · Cited by 323
“…maintenance, neuronal outgrowth and survival, learning and memory, as well as weight and sexual maintenance and regulation (Banks et al., 2012; Craft and Watson, 2004; De Felice et al., 2009; Dudek et al., 1997; Niswender and Schwartz, 2003; Ott et al., 2012; Plum et al., 2005; Porte et al., 2005).”
The PI3K/Akt signaling axis in Alzheimer’s disease: a valuable target to stimulate or suppress?
Razani, E., Pourbagheri‐Sigaroodi, A., Safaroghli‐Azar, A., Zoghi, A., Bavarsad, M. S., & Bashash, D. (2021) · Cell Stress and Chaperones · doi:10.1007/s12192-021-01231-3 · Cited by 232
“In consistence with this, De Felice et al. also delineated that Aβ 1 3 oligomer decreased the expression of membrane surface IRs through CK2 and CaMKII-dependent manner (Felice 2009).”
BackgroundInsulin receptor signaling in the development of neuronal structure and function
Chiu, S., & Cline, H. T. (2010) · Neural Development · doi:10.1186/1749-8104-5-7 · Cited by 231
“Furthermore, increasing evidence shows that Aβ binds to the insulin receptor, decreases the relative amount of insulin receptor in the dendritic compartment, and causes neuronal oxidative stress and loss of spines [153,169-171].”
Backgroundde Godoy, M. A., Saraiva, L. M., de Carvalho, L. R. P., Vasconcelos-dos-Santos, A., Beiral, H. J. V., Ramos, A. B., Silva, L. R. D. P., Leal, R. B., Monteiro, V. H. S., Braga, C. V., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.807180 · Cited by 214
Self-citationDecker, H., Lo, K. Y., Unger, S. M., Ferreira, S. T., & Silverman, M. A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1074-10.2010 · Cited by 221
“Although the mechanism of action of A Os at the plasma membrane is not known specifically, A Os can modulate NMDA and insulin receptors (De Felice et al., 2007, 2009).”
BackgroundSelf-citationInsulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease
Mullins, R. J., Diehl, T. C., Chia, C. W., & Kapogiannis, D. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00118 · Cited by 227
Zilberter, Y., & Zilberter, M. Y. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24064 · Cited by 222
“Insulin also blocks Ab binding to synapses, thereby preventing the ensuing neurotoxicity (De Felice et al., 2009; Xie et al., 2002) and Ab-induced loss of insulin receptors from neuronal dendrites (De Felice et al., 2009).”
BackgroundHong, S., Ostaszewski, B. L., Yang, T., O’Malley, T. T., Jin, M., Yanagisawa, K., Li, S., Bartels, T., & Selkoe, D. J. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.027 · Cited by 213
Clarke, J. R., Lyra e Silva, N. M., Figueiredo, C. P., Frozza, R. L., Ledo, J. H., Beckman, D., Katashima, C. K., Razolli, D., Carvalho, B. M., Frazão, R., et al. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404183 · Cited by 214
“AbOs were found to cause internalization and cellular redistribution of insulin receptors, to block downstream hippocampal insulin signaling (De Felice et al, 2009; Ma et al, 2009; Bomfim et al, 2012) and to cause hippocampal endoplasmic reticulum (ER) stress (Lourenco et al, 2013), establishing…”
BackgroundMethodSelf-citationBharadwaj, P., Wijesekara, N., Liyanapathirana, M., Newsholme, P., Ittner, L. M., Fraser, P. E., & Verdile, G. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161192 · Cited by 209
Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects
Frozza, R. L., Lourenco, M. V., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00037 · Cited by 213
“In addition, they promote tau hyperphosphorylation (De Felice et al., 2008; Jin et al., 2011), impaired axonal transport (Snyder et al., 2005; Decker et al., 2010b; Miñano-Molina et al., 2011; Bomfim et al., 2012), and drive inhibition of long-term potentiation (LTP) and memory impairment (Rowan et…”
BackgroundSelf-citationTahtouh, T., Elkins, J. M., Filippakopoulos, P., Soundararajan, M., Burgy, G., Durieu, É., Cochet, C., Schmid, R. S., Lo, D. C., Delhommel, F., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301034u · Cited by 213
Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function
Gladding, C. M., & Raymond, L. A. (2011) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2011.05.001 · Cited by 214
Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?
Stanley, M., Macauley, S. L., & Holtzman, D. M. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20160493 · Cited by 201
“In vitro studies show that synthetic AβOs co-cultured with neurons can bind to synapses and reduce dendritic spines, an effect that is rescued when treated with high insulin and IS is activated (De Felice et al., 2009).”
Correia, S. C., Santos, R. X., Carvalho, C., Cardoso, S., Candeias, E., Santos, M. S., Oliveira, C. R., & Moreira, P. I. (2012) · Brain Research · doi:10.1016/j.brainres.2011.12.063 · Cited by 202
Roles of AMP-activated Protein Kinase in Alzheimer’s Disease
Cai, Z., Yan, L., Li, K., Quazi, S. H., & Zhao, B. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8173-2 · Cited by 198
Potential Role of Glucagon-Like Peptide-1 (GLP-1) in Neuroprotection
Hölscher, C. (2012) · CNS Drugs · doi:10.2165/11635890-000000000-00000 · Cited by 198
Brain injury with diabetes mellitus: evidence, mechanisms and treatment implications
Hamed, S. A. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1293521 · Cited by 195
“amyloid β-oligomer-binding sites [209] and increased oligomer clearance [210], consequently preventing IR internaliza-”
BackgroundFigueiredo, C. P., Clarke, J. R., Ledo, J. H., Ribeiro, F. C., Costa, C., Melo, H. M., Mota-Sales, A. P., Saraiva, L. M., Klein, W. L., Sebollela, A. S., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0482-13.2013 · Cited by 186
“…neurons Previous studies have shown that A Os induce internalization of GluN1-containing NMDARs in cultured hippocampal neurons (Snyder et al., 2005; Lacor et al., 2007; De Felice et al., 2009; Jurgensen et al., 2011) without affecting total cellular levels of GluN1 (Jurgensen et al., 2011).”
BackgroundMethodResultSelf-citationImpaired insulin signalling and allostatic load in Alzheimer disease
Felice, F. G. D., Gonçalves, R. A., & Ferreira, S. T. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00558-9 · Cited by 183
Self-citationPereira Diniz, L., Tortelli, V., Matias, I., Morgado, J., Bérgamo Araujo, A. P., Melo, H. M., Seixas da Silva, G. S., Alves-Leon, S. V., de Souza, J. M., Ferreira, S. T., et al. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.3351-16.2017 · Cited by 171
“…been implicated in A Os binding to the excitatory synaptic terminal, including the NMDA (De Felice et al., 2007), insulin receptors (Zhao et al., 2008; De Felice et al., 2009), AMPA (Zhao et al., 2010), Wnt receptors (Magdesian et al., 2008), and PrP C (Laurén et al., 2009; Beraldo et al., 2016).”
BackgroundSelf-citationIntranasal Insulin for Alzheimer’s Disease
Hallschmid, M. (2021) · CNS Drugs · doi:10.1007/s40263-020-00781-x · Cited by 188
Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease
Paula‐Lima, A. C., Brito‐Moreira, J., & Ferreira, S. T. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12304 · Cited by 170
“…dysfunction (Saraiva et al. 2010; Paula-Lima et al. 2011; SanMartin et al. 2012), and disruption of fast axonal transport (Decker et al. 2010b) leading to synaptic dysfunction, synapse elimination and, ultimately, cell death (De Felice et al. 2007, 2009; Zhao et al. 2010; Renner et al. 2010; Fig.”
BackgroundResultSelf-citationMetabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease
Sun, Y., Ma, C., Sun, H. J., Wang, H., Wei, P., Zhou, Z., Wang, H., Pi, C., Shi, Y., & He, X. (2020) · Journal of Diabetes Research · doi:10.1155/2020/4981814 · Cited by 181
Barone, E., Domenico, F. D., Marzia Perluigi, A., & Butterfield, D. A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.09.006 · Cited by 182
Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach
Cholerton, B., Baker, L. D., Montine, T. J., & Craft, S. (2016) · Diabetes Spectrum · doi:10.2337/ds16-0041 · Cited by 192
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
“Since insulin can mitigate the synaptic loss of hippocampal neurons induced by amyloid beta [48] and regulate glycogen synthase kinase-3 beta, thereby inhibiting the phosphorylation of tau protein that forms neurofibrillary tangles which are a further pathological feature of AD [49], impaired CNS signaling of the horm…”
BackgroundDecker, 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 172
“Of relevance to the current study, we have recently shown that insulin blocks Ab oligomerbinding to synapses (De Felice et al. 2009).”
BackgroundInfluentialSelf-citationInsulin resistance and pathological brain ageing
Cholerton, B., Baker, L. D., & Craft, S. (2011) · Diabetic Medicine · doi:10.1111/j.1464-5491.2011.03464.x · Cited by 164
Intranasal insulin as a therapeutic option in the treatment of cognitive impairments
Benedict, C., Frey, W. H., Schiöth, H. B., Schultes, B., Jan Born, A., & Hallschmid, M. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.08.026 · Cited by 165
“3; (De Felice et al., 2009)].”
Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain
Perluigi, M., Pupo, G., Tramutola, A., Cini, C., Coccia, R., Barone, E., Head, E., Butterfield, D. A., & Di Domenico, F. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.007 · Cited by 155
“In addition, insulin resistance in AD might also be stimulated by Aβ monomers and soluble oligomers that bind to IRs, induce IR internalization in neurons and remove IR from dendrites [55,58–61], or inactivate IRS1 through the activation of JNK via TNFα [62,63].”
Roles of O-GlcNAc in chronic diseases of aging
Banerjee, P. S., Lagerlöf, O., & Hart, G. W. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.05.005 · Cited by 165
A Pilot Study of Exenatide Actions in Alzheimer’s Disease
Mullins, R. J., Mustapić, M., Chia, C. W., Carlson, O. D., Gulyani, S., Tran, J., Li, Y., Mattson, M. P., Resnick, S. M., Egan, J. M., et al. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190913155950 · Cited by 162
Metadata
- Authors
- 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.
- Affiliations
- Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; and
- Universidade Federal do Rio de Janeiro (BR)
- Instituto de Bioquímica Médica and
- Northwestern University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-02-10
- Volume
- 106
- Issue
- 6
- Pages
- 1971-1976
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2634809
- OpenAlex
- W2097335530
- Semantic Scholar
- f83fd1ab92993abebf2d284fe60d8398949b7908
- Cited by
- 657
- References
- 51
- Citations by year
- 2026: 11 · 2025: 27 · 2024: 17 · 2023: 20 · 2022: 30 · 2021: 41 · 2020: 41 · 2019: 42 · 2018: 44 · 2017: 42 · 2016: 44 · 2015: 53 · 2014: 44 · 2013: 57 · 2012: 46
- FWCI
- 31.69
- Type
- journal article
- Language
- en
- Update notices
- correction (2009-05-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Foundation for the National Institutes of Health
- Howard Hughes Medical Institute
- Alzheimer's Association
- American Health Assistance Foundation
- National Institute on Aging (R01AG022547, R01-AG22547, R01-AG18877, R01AG018877)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta oligomers, insulin signaling, insulin receptor, synaptic plasticity, oxidative stress, CaMKII, casein kinase 2, rosiglitazone, insulin receptor tyrosine kinase, hippocampal neurons, memory loss
- MeSH terms
- Rosiglitazone, Alzheimer Disease, Animals, Cattle, Cells, Cultured, Hippocampus, Humans, Insulin, Neurons, Protein Binding, Receptor, Insulin, Synapses, Signal Transduction, Amyloid beta-Peptides, Oxidative Stress, Dimerization, Protective Agents, Thiazolidinediones
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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 ›
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