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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).
plaindirect- Asserted: passes — The authors put it forward as true.
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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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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
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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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, 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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- It may state two separate claims as one. 7
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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
“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.
plaindirect- Asserted: passes — The authors put it forward as true.
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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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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
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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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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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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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It 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]
Citations
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1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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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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