. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem. 2007 Nov 16;282(46):33305-12. PubMed.


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  1. 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.

    View all comments by Sanjay Pimplikar
  2. 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.

    View all comments by Dennis Selkoe
  3. 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.


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

    View all comments by William Klein

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  1. How Does Aβ Do Harm? New Clues on Insulin Signaling, Spines, Inflammation