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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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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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).
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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).
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 7
- Probably not a substantial claim. 1
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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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“Beta-amyloid oligomers have been shown to interfere with insulin signaling [56], and since insulin is an important growth factor that also activates stem cells, this impairment in insulin signaling may be a reason for the impairment of stem cell proliferation found in the APP/PS1 mice [57,58].”
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“Moreover, insulin has been shown to mitigate pathological binding of amyloid-b–derived diffusible ligands (potent CNS neurotoxins) to synapses of neurons (14).”
BackgroundInteractions Between Age, Stress and Insulin on Cognition: Implications for Alzheimer's Disease
Solas, M., Aisa, B., Mugueta, M. C., Del Río, J., Tordera, R. M., & Ramírez, M. J. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.13 · Cited by 124
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The Early Events That Initiate β-Amyloid Aggregation in Alzheimer’s Disease
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Insulin resistance in Alzheimer's disease
Dineley, K. T., Jahrling, J. B., & Denner, L. A. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.09.001 · Cited by 125
“Elevated Aβ induces the removal of cell surface insulin receptors furthering insulin resistance (De Felice et al., 2009; Zhao et al., 2008).”
BackgroundProtein Tyrosine Phosphatase 1B (PTP1B): A Potential Target for Alzheimer’s Therapy?
Vieira, M. N. N., Silva, N. M. L. E., Ferreira, S. T., & Felice, F. G. D. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00007 · Cited by 123
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The dendritic hypothesis for Alzheimer's disease pathophysiology
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“[53] F.”
BackgroundInsulin resistance in Alzheimer's disease
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“Rosiglitazone potentiates the protective effects of insulin on cultured neurons and inhibits the production of Ab42 in mice, but evidence in human trials is inconclusive.(135,215,216) In addition, rosiglitazone has been shown to have anti-inflammatory effects decreasing levels of NFkB.”
BackgroundSynaptic Elimination in Neurological Disorders
Cardozo, P. L., de Lima, I. B. Q., Maciel, E. M. A., Silva, N. C., Dobránsky, T., & Ribeiro, F. M. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190603170511 · Cited by 115
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Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer‘s Disease
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Picone, P., Ditta, L. A., Sabatino, M. A., Militello, V., Biagio, P. L. S., Giacinto, M. L. D., Cristaldi, L., Nuzzo, D., Dispenza, C., Giacomazza, D., et al. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.11.057 · Cited by 119
Synaptic Dysfunction in Alzheimer’s Disease: Aβ, Tau, and Epigenetic Alterations
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Amyloid-β oligomers in cellular models of Alzheimer’s disease
Fontana, I. C., Zimmer, A. R., Rocha, A. S., Gosmann, G., Souza, D. O., Lourenco, M. V., Ferreira, S. T., & Zimmer, E. R. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15030 · Cited by 115
Self-citationAmyloid β and APP as biomarkers for Alzheimer’s disease
Zetterberg, H., Blennow, K., & Hanse, E. (2009) · Experimental Gerontology · doi:10.1016/j.exger.2009.08.002 · Cited by 118
“It has also been shown that A oligomers downregulate insulin receptors (De Felice et al., 2009).”
BackgroundOligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases
Forloni, G., Artuso, V., Vitola, P. L., & Balducci, C. (2016) · Movement Disorders · doi:10.1002/mds.26624 · Cited by 116
Role of Aβ in Alzheimer’s-related synaptic dysfunction
Zhang, H., Jiang, X., Ma, L., Wei, W., Li, Z., Chang, S., Wen, J., Sun, J., & Li, H. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.964075 · Cited by 157
The Essential Role of Soluble Aβ Oligomers in Alzheimer’s Disease
Wang, Z.-X., Tan, L., Liu, J., & Yu, J.-T. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9143-0 · Cited by 110
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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 113
“At sub-maximal doses of insulin, the PPARg agonist rosiglitazone (Rz) enhances the protective signaling effect (De Felice et al., 2009), likely a basis for the reported beneficial effects of Rz on cognition.”
BackgroundSelf-citationHallschmid, M. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12934 · Cited by 113
Bao, F., Wicklund, L., Lacor, P. N., Klein, W. L., Nordberg, A. K., & Marutle, A. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.05.003 · Cited by 112
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Alzheimer’s Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies
Shieh, J. C.-C., Huang, P.-T., & Lin, Y. (2020) · Molecular Neurobiology · doi:10.1007/s12035-019-01858-5 · Cited by 111
Is Alzheimer's disease related to metabolic syndrome? A Wnt signaling conundrum
Ríos, J. A., Cisternas, P., Arrese, M. A., Salesa Barja, Y., & Inestrosa, N. C. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2014.07.004 · Cited by 107
A Potential Link Between Visceral Obesity and Risk of Alzheimer’s Disease
Al-Kuraishy, H. M., Al-Gareeb, A. I., Alsayegh, A. A., Hakami, Z. H., Khamjan, N. A., Saad, H. M., Batiha, G. E., & WAARD, M. M. D. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03817-4 · Cited by 106
“In turn, high Aβ and NFTs reduce the expression of neuronal insulin receptors with the development of IR and further deterioration of AD pathology [84].”
BackgroundEffect of Apolipoprotein E Genotype and Diet on Apolipoprotein E Lipidation and Amyloid Peptides
Hanson, A. J., Bayer-Carter, J. L., Green, P. S., Montine, T. J., Wilkinson, C. W., Baker, L. D., Watson, G. S., Bonner, L. M., Callaghan, M., Leverenz, J. B., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.396 · Cited by 110
Dierssen, M., Fructuoso, M., de Lagrán, M. M., Marzia Perluigi, A., & Barone, E. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00670 · Cited by 106
“…of Aβ oligomers, which were demonstrated to induce brain IRS1 inhibition through a mechanism involving either reduced IR exposure at the plasma membrane (Zhao et al., 2008; De Felice et al., 2009; Forny-Germano et al., 2014) or increased ER stress via PKR (Lourenco et al., 2013) in AD (Figure 2).”
BackgroundMazucanti, C. H., Cabral‐Costa, J. V., Vasconcelos, A. R., Andreotti, D. Z., Scavone, C., & Kawamoto, E. M. (2015) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026615666150610125715 · Cited by 103
“IGF-1 receptor (IGFr) [280, 281].”
BackgroundGarwood, C. J., Ratcliffe, L. E., Morgan, S. V., Simpson, J. E., Owens, H., Vazquez-Villaseñor, I., Heath, P. R., Romero, I. A., Ince, P. G., & Wharton, S. B. (2015) · Molecular Brain · doi:10.1186/s13041-015-0138-6 · Cited by 101
“Several mechanisms have been implicated, for example changes in the phosphorylation state of IRS1, calpain overactivation and binding of Aβ-oligomers to IR [34–36].”
BackgroundHigaki, S., Muramatsu, M., Matsuda, A., Matsumoto, K., Satoh, J., Michikawa, M., & Niida, S. (2018) · PLoS ONE · doi:10.1371/journal.pone.0196929 · Cited by 103
How Can Insulin Resistance Cause Alzheimer’s Disease?
Yoon, J. H., Hwang, J., Son, S. U., Choi, J., You, S.-W., Park, H., Cha, S.-Y., & Maeng, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043506 · Cited by 106
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
Slow Excitotoxicity in Alzheimer's Disease
Ong, W.-Y., Tanaka, K., Dawe, G. S., Ittner, L. M., & Farooqui, A. A. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121990 · Cited by 106
Intranasal insulin in Alzheimer's disease: Food for thought
Chapman, C. D., Schiöth, H. B., Grillo, C. A., & Benedict, C. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.037 · Cited by 111
“Several lines of evidence converge to suggest that central insulin resistance plays a causal role in the development and progression of AD (Ma et al., 2009; De Felice et al., 2009).”
Davis, R. C., Marsden, I. T., Maloney, M. T., Minamide, L. S., Podlisny, M. B., Selkoe, D. J., & Bamburg, J. R. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-10 · Cited by 102
“Insulin helps neurons resist the pathogenic changes in cytoskeletal organization induced by Ab [67].”
BackgroundGIP has neuroprotective effects in Alzheimer and Parkinson’s disease models
Zhang, Z., & Hölscher, C. (2019) · Peptides · doi:10.1016/j.peptides.2019.170184 · Cited by 101
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
Alzheimer's disease: β‐amyloid plaque formation in human brain
Seeman, P. M., & Seeman, N. (2011) · Synapse · doi:10.1002/syn.20957 · Cited by 103
“…approximately 100 nM of b-amyloid-42 oligomers (but not monomers) selectively bind to synaptic junctions of specific neurons (De Felice et al., 2007, 2009; Lacor et al., 2004), inducing the loss of insulin receptors and N-methyl-D-aspartate receptors (Decker et al., 2010; De Felice et al., 2009).”
BackgroundRajasekar, N., Nath, C., Hanif, K., & Shukla, R. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0169-8 · Cited by 94
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 111
Self-citationMapping the brain in type II diabetes: Voxel-based morphometry using DARTEL
Chen, Z., Li, C., Sun, J., & Ma, L. (2011) · European Journal of Radiology · doi:10.1016/j.ejrad.2011.04.025 · Cited by 96
Role of Insulin Resistance in the Alzheimer's Disease Progression
Nguyen, T. T., Ta, Q. T. H., Nguyen, T. T. D., Le, T. T. H., & Giau, V. V. (2020) · Neurochemical Research · doi:10.1007/s11064-020-03031-0 · Cited by 103
Nunes‐Tavares, N., Santos, L. E., Stutz, B., Brito‐Moreira, J., Klein, W. L., Ferreira, S. T., & Mello, F. G. D. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.321448 · Cited by 96
Self-citationAmyloid-β Induces Hepatic Insulin Resistance by Activating JAK2/STAT3/SOCS-1 Signaling Pathway
Zhang, Y., Zhou, B., Zhang, F., Wu, J., Hu, Y., Liu, Y., & Zhai, Q. (2012) · Diabetes · doi:10.2337/db11-0499 · Cited by 92
Benedict, C., & Grillo, C. A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00215 · Cited by 101
“…including decreases in neuronal spine density and neurogenesis (Stranahan et al., 2008) and decreases in synaptic transmission (Kamal et al., 2013), whereas bolstering insulin signaling mitigates Aβ-induced synapse loss in mature cultures of hippocampal neurons (De Felice et al., 2009).”
BackgroundAmyloid-β Triggers the Release of Neuronal Hexokinase 1 from Mitochondria
Saraiva, L. M., Seixas da Silva, G. S., Galina, A., da-Silva, W. S., Klein, W. L., Ferreira, S. T., & De Felice, F. G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015230 · Cited by 94
“Ab oligomers accumulate in the brains of AD patients [32,33] and have been linked to major AD pathology hallmarks, including neuronal tau hyperphosphorylation [24], oxidative stress [14,15] and synapse deterioration [25].”
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Increased occurrence of protein kinase CK2 in astrocytes in Alzheimer’s disease pathology
Rosenberger, A. F. N., Morrema, T. H. J., Gerritsen, W. H., van Haastert, E. S., Snkhchyan, H., Hilhorst, R., Rozemüller, A. J. M., Scheltens, P., van der Vies, S. M., & Hoozemans, J. J. M. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0470-x · Cited by 99
Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Froestl, W., Muhs, A., & Pfeifer, A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121186 · Cited by 94
A Review: Treatment of Alzheimer’s Disease Discovered in Repurposed Agents
Appleby, B. S., Nacopoulos, D. A., Milano, N. J., Zhong, K., & Cummings, J. L. (2013) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000345791 · Cited by 90
Batista, A. F., Rody, T., Forny-Germano, L., Cerdeiro, S., Bellio, M., Ferreira, S. T., Munoz, D. P., & De Felice, F. G. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02099-x · Cited by 91
Self-citationBiliverdin Reductase-A Mediates the Beneficial Effects of Intranasal Insulin in Alzheimer Disease
Barone, E., Tramutola, A., Triani, F., Calcagnini, S., Di Domenico, F., Ripoli, C., Gaetani, S., Grassi, C., Butterfield, D. A., Cassano, T., et al. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1231-5 · Cited by 86
Metabolic Dysfunction in Alzheimer’s Disease: From Basic Neurobiology to Clinical Approaches
Clarke, J. R., Ribeiro, F. C., Frozza, R. L., Felice, F. G. D., & Lourenco, M. V. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179911 · Cited by 93
Self-citationInsulin signalling in Alzheimer′s disease and diabetes: from epidemiology to molecular links
Ribé, E. M., & Lovestone, S. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12534 · Cited by 88
The Prion Protein Ligand, Stress-Inducible Phosphoprotein 1, Regulates Amyloid-β Oligomer Toxicity
Ostapchenko, V. G., Beraldo, F. H., Mohammad, A. H., Xie, Y., Hirata, P. H. F., Magalhães, A. C., Lamour, G., Li, H., Maciejewski, A., Belrose, J. C., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3214-13.2013 · Cited by 87
“3A,C) as described previously (De Felice et al., 2007, 2009).”
MethodSelf-citationPathogenesis of Abeta Oligomers in Synaptic Failure
Sivanesan, S., Tan, A., & Rajadas, J. (2013) · Current Alzheimer Research · doi:10.2174/1567205011310030011 · Cited by 85
“The loss of surface insulin receptors (IRs) at the synapse by A oligomers or ADDLs [39] involves altered IR tyrosine autophosphorylation [37] and a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition [117] apart from the loss of activation of specific kinases re…”
BackgroundEphA4 Activation of c-Abl Mediates Synaptic Loss and LTP Blockade Caused by Amyloid-β Oligomers
M. Vargas, L., Leal, N., Estrada, L. D., González, A., Serrano, F., Araya, K., Gysling, K., Inestrosa, N. C., Pasquale, E. B., & Alvarez, A. R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092309 · Cited by 85
Amyloid-β Oligomers Induce Differential Gene Expression in Adult Human Brain Slices
Sebollela, A. S., Freitas-Corrêa, L., de Oliveira, F. F., Paula-Lima, A. C., Saraiva, L. M., Martins, S. M., Mota, L. D. C., Torres, C., Alves‐Leon, S. V., de Souza, J. M., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.298471 · Cited by 90
“At the cellular level, A Os have been shown to induce insulin receptor internalization and the impairment of neuronal insulin signaling in hippocampal cultures (18, 19).”
BackgroundSelf-citationPitt, J. E., Wilcox, K. C., Tortelli, V., Diniz, L. P., Oliveira, M. S., Dobbins, C., Yu, X., Nandamuri, S., Gomes, F. C. A., DiNunno, N., et al. (2017) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-06-0416 · Cited by 87
“These findings confirm and extend previous indications that insulin signaling protects neurons against AβOs and AD pathogenesis (Townsend et al., 2007; Jolivalt et al., 2008; De Felice et al., 2009; Zhao et al., 2009; Craft et al., 2012; Long-Smith et al., 2013).”
BackgroundResultInfluentialSelf-citationDeregulation of brain insulin signaling in Alzheimer’s disease
Chen, Y., Deng, Y., Zhang, B., & Gong, C. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1408-x · Cited by 82
Brito-Moreira, J., Lourenco, M. V., Oliveira, M. M., Ribeiro, F. C., Ledo, J. H., Diniz, L. P., Vital, J. F. S., Magdesian, M. H., Melo, H. M., Barros-Aragão, F., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.761189 · Cited by 84
“In line with previous studies (8, 28), exposure of hippocampal neurons to A Os for 24 h reduced the density of dendritic spines.”
MethodResultSelf-citationBertram, S., Brixius, K., & Brinkmann, C. K. (2016) · Endocrine · doi:10.1007/s12020-016-0976-8 · Cited by 89
Steculorum, S. M., Solas, M., & Brüning, J. C. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.12.008 · Cited by 82
“[51] De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT,”
InfluentialGut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide
Candeias, E. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i6.807 · Cited by 86
Dutta, B. J., Singh, S., Seksaria, S., Gupta, G. D., & Singh, A. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106358 · Cited by 89
Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2
Zhang, Y., Zhou, B. Z., Deng, B., Zhang, F., Wu, J., Wang, Y., Le, Y., & Zhai, Q. (2012) · Diabetes · doi:10.2337/db12-0670 · Cited by 85
Immune and Neuroprotective Effects of Physical Activity on the Brain in Depression
Phillips, C., & Fahimi, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00498 · Cited by 89
“…circuit structure and function (via transmitter receptor trafficking), and plasticity (via alterations in synapse density) (Chiu et al., 2008), effects that may be particularly important in the aging hippocampus (Zhao et al., 2008; De Felice et al., 2009) given its importance for HPA regulation.”
BackgroundImpaired peripheral glucose homeostasis and Alzheimer's disease
Wijesekara, N., Gonçalves, R. A., Felice, F. G. D., & Fraser, P. E. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.027 · Cited by 84
Self-citation
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
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