The amyloid hypothesis of Alzheimer disease, at its simplest, posits that accumulation of amyloid-β (Aβ) protein in the brain results in neuronal dysfunction and death, leading eventually to dementia. The idea of amyloid toxicity has driven much research, but fundamental gaps remain, starting with the question of exactly how Aβ is toxic to neurons. A host of studies has created some consensus that excess Aβ is bad for synaptic function and neuronal survival, but no one mechanism has broken through as “the” cause for AD.

This week, two papers offer similar takes on how soluble Aβ interferes with insulin signaling, and might even avail itself of the insulin receptor to poison synapses. A third study explores the links between Aβ and the development of dendritic spines, and a fourth between Aβ and inflammation. Below is an update.

The newest finding, out yesterday online as a paper in press in the Journal of Biological Chemistry, implicates the insulin receptor and its signaling cascades in the shutdown of long-term potentiation induced by Aβ. In the study, Matthew Townsend (who since moved to Merck Research Labs in Boston), Tapan Mehta, and Dennis Selkoe at Harvard Medical School detected LTP inhibition in cultured primary hippocampal neurons after transient treatment with low concentrations of soluble Aβ oligomers. The scientists found that Aβ blocked activation of three kinases that are normally turned on during LTP induction, i.e., calmodulin dependent kinase II (CaMKII), Erk/MAPK, and Akt/PKB, while leaving alone PKA and PKC.

This pattern of selective inhibition matched that elicited by an insulin receptor kinase inhibitor (AG1024), which, like Aβ, inhibited LTP. This led the researchers to ask if Aβ acts through the insulin receptor to squelch LTP. In support of this idea, they show that soluble Aβ binds to the insulin receptor, inhibiting its autophosphorylation. In addition, excess insulin could partially reverse the inhibitory effects of Aβ on both kinase activation and LTP. This observation, they write, “supports the hypothesis that Aβ and insulin share common signal transduction pathways and that at least one aspect of Aβ-mediated synaptotoxicity may be through disruption of insulin signaling, either directly or indirectly.”

That is also the idea of a paper from William Klein’s lab at Northwestern University in Evanston, Illinois, published online August 24 in the FASEB Journal. Their data show that Aβ treatment results in a loss of insulin signaling, though perhaps through a different mechanism. First author Wei-Qin Zhao demonstrates that treating hippocampal neurons in culture with soluble Aβ oligomers (in their parlance, ADDLs), results in a loss of most dendritic insulin receptors. Redistribution of the receptors to the cell body greatly diminishes the cells’ response to insulin, and triggers an increase in phosphorylation of the Akt kinase at Ser473, a hallmark of insulin resistance in other diseases. As this group has shown for other ADDL-induced effects, the downregulation of insulin receptors depended on NMDA receptor activity (see ARF related news story). “These results identify novel factors that affect neuronal IR signaling and suggest that insulin resistance in AD brain is a response to ADDLs, which disrupt insulin signaling and may cause a brain-specific form of diabetes as part of an overall pathogenic impact on CNS synapses,” Zhao and colleagues write.

In the brain, insulin’s functions reach beyond glucose homeostasis to include synaptotrophic and neurotrophic effects. These new studies jibe with an emerging concept that neuronal insulin resistance is an important part of the pathology of AD (see ARF live discussion and ARF live discussion), and raise the possibility that Aβ oligomers may directly induce insulin resistance in neurons.

Whatever its early stages, one downstream result of Aβ’s assault on the brain is the massive synaptic loss that correlates with the cognitive decline of AD. A third paper, this one from Brad Hyman’s lab at the Massachusetts General Hospital in Boston shows that Aβ destabilizes dendritic spines, the neuronal protrusions that harbor synapses. To look at spine dynamics, first author Tara Spires-Jones and colleagues used in-vivo multiphoton microscopy to watch spines in the brains of living mice over an hour’s time. They found that even in aged control animals, most spines are stable, but a small proportion is in flux. These latter spines appear and disappear in equal numbers, keeping the total number steady. However, in Tg2576 APP-overproducing mice, the picture was different. In the neighborhood of amyloid plaques, disappearance of spines outstripped formation, leading to a net loss in spine density. Spines farther away from plaques were not disrupted. The authors propose that the plaques act as a source of diffusible soluble Aβ—which has been shown to change the composition of synaptic receptors (see ARF related news story) and the stability of synapses (see ARF related news story and ARF news story) in cultured neurons and in mouse brain in vivo. Their results indicate that the brain maintains its plasticity with age, but not in the presence of Aβ.

Finally, an enduring question concerning Aβ toxicity lies in the peptide’s propensity to induce neuroinflammation. It raises the question of the relative lethality of Aβ’s direct actions on neurons, versus its indirect assault via harmful inflammatory reactions. Recently, Yong Shen and colleagues at the Sun Health Research Institute, Sun City, Arizona, showed that the receptor for an important inflammatory mediator, tumor necrosis factor α (TNFα) was required for Aβ-induced neuronal death (Li et al., 2004). The receptor, the tumor necrosis factor type I receptor (TNFR1), is wired into the apoptotic machinery of cells, and functions as a death receptor.

Now, the same group shows that TNFR1 also plays a role in Aβ generation. In the August 27 Journal of Cell Biology, first authors Ping He and Zhenyu Zhong report that deleting the TNFR1 in App23 mice profoundly decreases Aβ generation and subsequent amyloid pathology. Compared with the parental line, the knockout mice had 80 percent fewer hippocampal amyloid plaques, less microglial activation, reduced neuronal loss, and better performance on memory tests. The effect appeared to stem from a reduction in β-secretase protein and activity, which was under the control of TNFα, the ligand for the TNFR1.

“These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved with APP processing and Aβ plaque formation,” the authors write. The work indicates that TNFα might be part of a positive feedback loop, where Aβ induces inflammation and TNF production, which then further increases Aβ production by boosting β-secretase. Blocking TNFR1 could present a new therapeutic target for AD, they conclude.—Pat McCaffrey


  1. APP is so ubiquitously expressed, it would be interesting to know whether this same effect of ADDLs on insulin receptors is found in other organs.

    View all comments by Paul Coleman
  2. The two papers that report the effects of “oligomeric” Aβ on insulin signaling pathways display a curious discrepancy. Townsend et al. add their oligomeric Aβ preparation to mouse hippocampal neuronal cultures and observe no effect of Aβ alone on S473 phosphorylation of Akt. Zhao et al. add their oligomeric Aβ preparation to rat hippocampal neurons and observe a whopping increase in S473 phosphorylation of Akt. Aren't these observations inconsistent, or are we missing something? These findings would seem to mean that the “Selkoe-mers” and the “Klein-mers” elicit their effects through different mechanisms? If so, which pathway is followed by the “real-mers”' implicated in human AD? At this point, we have no data yet on how the “star-oligomers” will affect the phosphorylation of Akt.

    Zhao et al. state that phosphorylation of Akt at S473 is a hallmark of insulin resistance. I'd like to point out that phosphorylation of Akt at S473 is an indicator of its activation and widely accepted as such in the field (Hemmings, 1997). So, could one interpret these findings to suggest that the oligomeric Aβ activates the Akt signaling pathway and promotes cell survival (Chan et al., 1999)? That would run against everything we were told about Aβ. To be fair, the authors do speculate about “a possible negative feedback loop,” but their observations, at first glance, demonstrate activation of Akt by “oligomeric Aβ.”


    . Akt signaling: linking membrane events to life and death decisions. Science. 1997 Jan 31;275(5300):628-30. PubMed.

    . AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem. 1999;68:965-1014. PubMed.

  3. Comment by Matt Townsend and Dennis Selkoe
    In response to Sanjay Pimplikar's comment, we fully agree that it will be important to clarify the differences between our manuscripts—whether it's the source of Aβ, the concentration, the age of the neurons, etc. Nevertheless, the basic conclusion of both papers is consistent, namely, that Aβ oligomers interfere with insulin receptor function in neurons. The purpose of neuronal insulin receptors is largely unexplored, although C. Ronald Kahn and colleagues have reported significant tauopathy (but not memory deficits) in the NIRKO mice (Schubert et al., 2004).

    We find two important differences between our work and that of Zhao et al. The first, of course, is the opposite effects on Akt phosphorylation; the second is the issue of whether Aβ prevents insulin receptor signaling by blocking the receptor versus causing receptor internalization. The simplest explanation is a subtle difference in methods. However, a perhaps more satisfying possibility is that picomolar concentrations of Aβ simply shut down insulin receptor signaling cascades, while nanomolar concentrations have a more dire effect, such as inducing insulin receptor internalization and stimulating an Akt-driven checkpoint as to whether to survive or undergo apoptosis. If this is the case, both observations may be relevant for Alzheimer disease.

    A second notable possibility pertains to our unpublished observation that monomeric Aβ may act as a weak agonist at the insulin receptor. Depending on the exact levels of monomeric Aβ in both of our preparations, we might expect to see precisely the opposite effect. A distinct effect of monomeric versus oligomeric Aβ on the insulin receptor may conform with widely accepted notions that the conformation of Aβ is important for toxicity. In this scenario, monomeric Aβ may mildly stimulate insulin receptor activity, while oligomeric Aβ antagonizes its function.

    Following this line of reasoning into speculation, it's conceivable that the common sequence and conformational elements that enable insulin degrading enzyme (IDE) to degrade both insulin and monomeric Aβ are common to the insulin receptor, as well. Should this be the case, the evolutionary importance of IDE in degrading Aβ may outweigh its unfortunate side effects in the insulin receptor.


    . Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3100-5. PubMed.

  4. We acknowledge Dr. Pimplikar's understandable concern regarding Akt. We would like to call attention to the very nice editorial by Rong Tian in Circulation Research (Tian, 2005), which explains the emerging complexities of Akt ("Another Role for the Celebrity: Akt and Insulin Resistance"). Tian's is an important commentary. In his words, "Although thr 308 phosphorylation of the Akt resulted in increased glucose uptake, Akt activation by Ser 473 phosphorylation acted as a negative regulator that phosphorylated a threonine on the insulin receptor β-subunit causing decreased autophosphorylation of the receptors…. This finding suggests a likely mechanism for insulin resistance...." In our Results section, we cite this commentary, and we state that "Inhibition of IR autophosphorylation can occur physiologically through negative feedback regulation by Akt." In our Discussion, we include further citations germane to this topic to provide a knowledge base relevant to insulin receptor resistance in the context of elevated Akt-pSer473. Observations are presented "suggesting the possibility that elevated Akt-pSer473 induced Aβ oligomers could contribute to insulin resistance in AD-affected brain." Our hypothesis concerning possible involvement of Akt phosphorylation in ADDL-induced insulin resistance thus derives from published precedents.

    The correlation between oligomer structures and neurotoxic activities is of fundamental concern. It would be appropriate to address this important issue at length at a meeting or online. We would be interested in carrying out a compare-and-contrast discussion, or better yet, collaborative experimentation. Historically, we note that with our colleagues Tuck Finch and Grant Krafft, we introduced evidence that small soluble oligomers of the fibrillogenic Aβ peptide could be potent CNS neurotoxins, capable of rapidly attacking synaptic plasticity (LTP) and ultimately killing neurons (Lambert et al., 1998). We coined the ADDL nomenclature to distinguish globular oligomeric toxins from fibrillar Aβ and to introduce a mechanism for dementia based on pathogenic ligand binding and disrupted signal transduction. Using conformation-specific antibodies generated by ADDLs (Lambert et al., 2001), we found that Alzheimer’s-affected human brain (Gong et al., 2003) and CSF (Georganopoulou et al., 2005) present significantly elevated ADDL levels.

    The relationship between various oligomers needs further investigation, but synthetic and brain-derived ADDLs show overlapping features. Both show prominent 12mers (54 kDa) that react with the conformation-specific antibodies (Gong et al., 2003). Both bind with great specificity to particular synapses, acting as gain-of-function pathogenic ligands (Lacor et al., 2004). Both stimulate AD-type tau hyperphosphorylation (De Felice et al., 2007). Given the structural diversity of Aβ oligomers (Chromy et al., 2003), we are open-minded about the possibility that distinct brain-derived oligomers could interact differentially with brain cells to produce unique aspects of neural damage.


    . Another role for the celebrity: Akt and insulin resistance. Circ Res. 2005 Feb 4;96(2):139-40. PubMed.

    . Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. PubMed.

    . Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies. J Neurochem. 2001 Nov;79(3):595-605. PubMed.

    . Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2273-6. PubMed.

    . Synaptic targeting by Alzheimer's-related amyloid beta oligomers. J Neurosci. 2004 Nov 10;24(45):10191-200. PubMed.

    . Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging. 2008 Sep;29(9):1334-47. PubMed.

    . Self-assembly of Abeta(1-42) into globular neurotoxins. Biochemistry. 2003 Nov 11;42(44):12749-60. PubMed.

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News Citations

  1. Aβ Oligomers and NMDA Receptors—One Target, Two Toxicities
  2. Amyloid-β Zaps Synapses by Downregulating Glutamate Receptors
  3. AMPA Receptors: Going, Going, Gone in Aβ-exposed Synapses, PSD95 Knockouts
  4. Aβ—Three Places, Three Ways of Wreaking Havoc

Paper Citations

  1. . Tumor necrosis factor death receptor signaling cascade is required for amyloid-beta protein-induced neuron death. J Neurosci. 2004 Feb 18;24(7):1760-71. PubMed.

Other Citations

  1. ARF live discussion

Further Reading

Primary Papers

  1. . Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem. 2007 Nov 16;282(46):33305-12. PubMed.
  2. . Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008 Jan;22(1):246-60. PubMed.
  3. . Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model. Am J Pathol. 2007 Oct;171(4):1304-11. PubMed.
  4. . Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol. 2007 Aug 27;178(5):829-41. PubMed.