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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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“Insulin, measured through insulin receptor (IR) activity, was found to mitigate synaptic degradation in the presence of soluble Aβ oligomers (De Felicea et al., 2009).”
BackgroundOstapchenko, V. G., Beraldo, F. H., Guimarães, A. L. S., Mishra, S., Guzmán, M. S., Fan, J., Martins, V. R., Prado, V. F., & Prado, M. A. M. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12296 · Cited by 38
“Dihydroxyphenylglycine (DHPG, 50 lM), 1 lM Ab oligomers- prepared as described previously (De Felice et al. 2009; Caetano et al. 2011)- and/or 100 lM LY 367385 (mGluR1 antagonist, Tocris Bioscience, Southampton, UK) were added to 8 DIV neurons.”
BackgroundMethodRoselli, F., Livrea, P., & Almeida, O. F. X. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023097 · Cited by 38
“, other Aβ effects, such as NMDAR and Insulin receptors”
BackgroundNeuroprotective action of proline-rich polypeptide-1 in β-amyloid induced neurodegeneration in rats
Yenkoyan, K. B., Safaryan, K., Chavushyan, V. A., Meliksetyan, I. B., Navasardyan, G., Sarkissian, J. S., Galoyan, A. A., & Aghajanov, M. I. (2011) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.08.003 · Cited by 37
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A review of brain insulin signaling in mood disorders: From biomarker to clinical target
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“In addition, in vitro studies have shown that addition of metformin to insulin synergistically enhances Aβ degradation (Chen et al. 2009a, b), and addition of rosiglitazone to insulin reverses the downregulation of the insulin receptor by Aβ oligomers (De Felice et al. 2009).”
Santiago, J. C. P., & Hallschmid, M. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.03.007 · Cited by 37
Therapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection
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Kang, M., Kim, S. Y., An, S. S. A., & Ju, Y. R. (2013) · Experimental & Molecular Medicine · doi:10.1038/emm.2013.63 · Cited by 37
Study of the effect of inhibiting galanin in Alzheimer's disease induced in rats
Baraka, A., & ElGhotny, S. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.05.030 · Cited by 37
“At submaximal insulin doses, protection was potentiated by rosiglitazone (De Felice et al., 2009).”
BackgroundChen, Y., Wei, G., Nie, H., Lin, Y., Tian, H., Liu, Y., Yu, X., Cheng, S., Yan, R., Wang, Q., et al. (2014) · Brain Research · doi:10.1016/j.brainres.2014.01.005 · Cited by 38
Exploiting Common Aspects of Obesity and Alzheimer’s Disease
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Cortical thinning in type 2 diabetes mellitus and recovering effects of insulin therapy
Chen, Z., Sun, J., Yang, Y., Lou, X., Wang, Y., Wang, Y., & Ma, L. (2014) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2014.07.014 · Cited by 36
“It has been demonstrated that insulin can prevent the pathogenic binding of Ab oligomers to sites localized at the hippocampal nerve cell synapses, and this insulin protection is potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes [5].”
BackgroundXu, S., Guilan, L., Bao, X., Wu, J., Li, S., Zheng, B., Anwyl, R., & Wang, Q. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-130680 · Cited by 35
“Soluble A oligomers bind to synapses and trigger activation of downstream signal pathways, and cause neuronal tau hyperphosphorylation, oxidative stress, and synapse deterioration and loss [18, 33, 34].”
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Intranasal Neuropeptide Administration To Target the Human Brain in Health and Disease
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Weiss, C., & Disterhoft, J. F. (2015) · Behavioral Neuroscience · doi:10.1037/bne0000061 · Cited by 36
“…and his colleagues support the hypothesis that defective insulin signaling is a major contributor to the pathology associated with AD (Zhao et al., 2009; De Felice et al., 2009; Bomfim et al., 2012), including the pathology found in rabbits that develop diabetes following an injection of Alloxan.”
BackgroundSebollela, A. S., Cline, E. N., Popova, I. A., Luo, K., Sun, X., Ahn, J., Barcelos, M. A., Bezerra, V. N., Silva, N. M. L. E., Patel, J., et al. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14118 · Cited by 38
“Neuroprotection by NUsc1 was tested by analyzing its capacity to block or reduce AbO-induced toxic events in rat hippocampal neurons, namely excessive ROS accumulation (De Felice et al. 2007, 2009) and tau hyperphosphorylation (De Felice et al. 2008).”
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Minireview: Food for Thought: Regulation of Synaptic Function by Metabolic Hormones
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Attenuation of insulin signalling contributes to FSN‐1‐mediated regulation of synapse development
Hung, W., Hwang, C., Gao, S., Liao, E. H., Chitturi, J., Wang, Y., Li, H., Stigloher, C., Bessereau, J., & Zhen, M. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.91 · Cited by 32
“Impaired insulin and IGF-signalling-mediated synaptic dysfunction has been further implicated in neurological disorders, including Alzheimer’s disease (Gault and Holscher, 2008; De Felice et al , 2009; Lee et al , 2009) and Rett Syndrome (Liao and Xu, 2009; Tong et al , 2009; Tropea et al , 2009).”
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“…and symptom progression in dementia has been slowed with drugs potentiating insulin signaling in rodents and in humans (Gudala et al. 2013; Moreira 2012; Bobsin and Kreienkamp 2015; Cooper et al. 2015; Bomfim et al. 2012; De Felice et al. 2009; Escribano et al. 2010; Querfurth and LaFerla 2010).”
BackgroundWilcox, K. C., Marunde, M. R., Das, A., Velasco, P. T., Kuhns, B. D., Marty, M. T., Haoming, J., Luan, C.-H., Sligar, S. G., & Klein, W. L. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125263 · Cited by 37
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“Several reports showed that TZDs have ameliorating effects on impaired learning and memory and on aggregated Ab in AD animal and cell models (Pedersen et al. 2006; De Felice et al. 2009; Escribano et al. 2010).”
BackgroundHan, X., Yang, L., Du, H., Sun, Q., Wang, X., Cong, L., Liu, X., Yin, L., Li, S., & Du, Y. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0268-5 · Cited by 36
“…et al. 2012); groups III, IV, and V were treated with 100 nM human recombinant insulin (Novo Nordisk, Bagsvard, Denmark) for 30 min after the treatments with DMEM vehicle, 100 nM Ab 1–42 oligomers and 1 lM Ab 1–42 oligomers, respectively (Bomfim et al. 2012; De Felice et al. 2009; Ji et al. 2011).”
Takach, O. P., Gill, T. B., & Silverman, M. A. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.11.018 · Cited by 34
“AbOs lead to the loss of cell surface insulin receptors (IR), deregulating downstream effectors in the insulin pathway (De Felice et al., 2009, 2014).”
Kreis, P., Gallrein, C., Puente, E. R., Mack, T. G. A., Kroon, C., Dinkel, V., Willmes, C. G., Murk, K., Dieck, S. T., Schuman, E. M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08420-w · Cited by 35
The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention
Merlo, S., Spampinato, S. F., Caruso, G. I., & Sortino, M. A. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200131105418 · Cited by 35
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“Drug treatments enhancing GLP-1 activity hold out hope for treatment and prevention of Alzheimer’s disease (AD) and cognitive decline.”
BackgroundArab, L., Sadeghi, R., Walker, D. G., Lue, L.-F., & Sabbagh, M. N. (2011) · Current Neuropharmacology · doi:10.2174/157015911798376334 · Cited by 35
“In a study to test the hypothesis that insulin signaling provides a protective mechanism against ADDLs toxicity, it was shown that the neurotoxic effects of ADDLs could be competitively inhibited with insulin, or with suboptimal doses of insulin combined with the insulin receptor sensitizing drug rosiglitozone, by blo…”
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A method to determine insulin responsiveness in synaptosomes isolated from frozen brain tissue
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Lipid microdomain modification sustains neuronal viability in models of Alzheimer’s disease
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Glimepiride attenuates Aβ production via suppressing BACE1 activity in cortical neurons
Liu, F., Wang, Y., Yan, M., Zhang, L., Pang, T., & Liao, H. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.10.052 · Cited by 33
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Sleep Disturbances and Cognitive Impairment in the Course of Type 2 Diabetes-A Possible Link
Brzecka, A., Madetko‐Alster, N., Nikolenko, V. N., Ashraf, G. M., Ejma, M., Leszek, J., Daroszewski, C., Sarul, K., Михалева, Л. М., Somasundaram, S. G., et al. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200309101750 · Cited by 35
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“The observed neuroprotection by these chemokines could be due to direct abrogation of the binding of Aβ oligomers by down regulation of their binding sites on neurons as observed in the case of activation of the insulin receptor by insulin (De Felice et al., 2009).”
BackgroundAβ inhibits SREBP-2 activation through Akt inhibition
Mohamed, A., Viveiros, A., Williams, K., & Chaves, E. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m076703 · Cited by 35
Antidiabetic therapies and Alzheimer disease.
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Self-citationBased on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies
Yang, H., Li, J., Li, X., Ma, L., Hou, M., Zhou, H., & Zhou, R. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.927530 · Cited by 33
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“…and memory (Townsend et al., 2007; Freiherr et al., 2013) and provides a physiological defense mechanism against oligomer-induced synapse loss (De Felice et al., 2009) and furthermore protects neurons from the accumulation of hyperphosphorylated τ (Escribano et al., 2010), suggesting that IR…”
BackgroundAlbumin Exchange in Alzheimer's Disease: Might CSF Be an Alternative Route to Plasma?
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“A process of synaptic remodelling suspected to be involved in memory consolidation.(40,41)”
Chacon, P. J., Garcia-Mejias, R., & Rodriguez-Tebar, A. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-14 · Cited by 28
“Still, recent publications have reinforced the notion that Ab interferes with insulin signalling [6] and indeed, when soluble forms of Ab bind to dendrites, they provoke the removal of insulin receptors (probably by activating their internalization), as well as preventing synapse formation [7].”
BackgroundRole of anti-diabetic drugs as therapeutic agents in Alzheimer's disease
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“The accumulation of these aggregates triggers a variety of responses detrimental to neuron plasticity and memory viz oxidative stress, loss of spines and receptors (De Felice et al., 2009).”
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“Aβ may induce ChAT inhibition through N-methyl-D-aspartic acid (NMDA) receptors or insulin signaling mechanisms [27,28].”
BackgroundGlaucoma – Diabetes of the brain: A radical hypothesis about its nature and pathogenesis
Faiq, M. A., Dada, R., Saluja, D., & Dada, T. (2014) · Medical Hypotheses · doi:10.1016/j.mehy.2014.02.005 · Cited by 27
“causing OS [87,88] leading to mitochondrial involvement and neuronal cell death.”
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Hippocampal insulin resistance and altered food decision-making as players on obesity risk
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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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