. Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured hippocampal neurons. J Neurosci. 2010 Jul 7;30(27):9166-71. PubMed.

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  1. Functional and structural alterations in synapses and axons represent an early feature of Alzheimer disease. Given the critical role of fast axonal transport (FAT) in the maintenance of these neuronal compartments, Decker et al. elaborate on a central question: Does Aβ affect FAT? In line with previous studies, these authors report a dramatic reduction in FAT of mitochondria and of vesicle-associated BDNF in hippocampal neurons incubated with Aβ. Such inhibition would unquestionably lead to neuronal dysfunction and eventually death. Unfortunately, the authors used a concentration of Aβ that likely is well above physiological and possibly also pathological levels. In this regard, it will be interesting to evaluate the effect of Aβ at much lower concentrations.

    Significantly, Decker et al. provide convincing experimental evidence that the inhibitory effect of Aβ on FAT involves activation of GSK3β through activation of NMDR receptors. Pathogenic targets of GSK3β relevant to its inhibitory effect on FAT are not addressed in this work. However, previous studies by the groups of Drs. Morfini and Brady (Morfini et al., 2002) suggest that the major motor protein, conventional kinesin, could represent one such target. An important future step would be to establish the contribution of this mechanism to the beneficial effect of memantine on AD patients.

  2. This is an interesting and well-presented study, but as with many studies of Aβ toxicity, the dose used is extremely high and may not recapitulate what occurs in the human brain in patients with AD. Extrapolation from cell culture to the human disease is always risky business for the AD field. However, the concept of a defect in axonal transport continues to be an important issue independent of whether or not Aβ initiates this event.

  3. We intended to comment on this interesting paper from the Silverman lab prior to leaving for ICAD 2010, held in the beautiful island of Oahu, Hawaii, but time constraints made us postpone the submission of our comments. This turned out to be a good thing, because we now can integrate in our comment with new results presented at this meeting.

    The idea that extracellular Aβ is in many ways toxic for neurons is no longer new, and is supported by solid results from many laboratories. One of these toxic effects targets axonal transport (1). Although the transport of mitochondria is particularly vulnerable to the presence of Aβ in the extracellular space (2), it is likely that axonal transport of many cargoes becomes impeded, as suggested by earlier studies (3,4). Previous studies have investigated the effect of monomeric and fibrillar Aβ on axonal transport, but—except for an ex-vivo study done in squid axoplasm (6)—did not specifically examine the effect of the diffusible Aβ oligomeric species, which are currently considered to be most relevant for the pathogenic mechanisms in Alzheimer disease (6).

    This gap is now filled by the present study, which uses hippocampal neurons in primary culture to convincingly show that the Aβ oligomers are indeed disturbing axonal transport of at least two types of cargo: dense-core vesicles and mitochondria. This study also provides some hints on the mechanism by which Aβ exerts this effect: by aberrant activation of the NMDA receptor and GSK3β signaling pathways. Both pathways have been previously proposed to mediate a toxic effect of Aβ on neurons.

    While the present paper mostly presents data that are consistent with previous studies that show a block of axonal transport triggered by applied Aβ (2-5), it also differs in some important aspects. For example, in the present study, the effect of applied Aβ on the motility of mitochondria is slow, with minimal effect at four hours of treatment; in a previous study, the effect was acute, being observed at 10-30 minutes after application of Aβ (2). Also, while this study shows that the block of axonal transport caused by Aβ occurs via an NMDA receptor-dependent mechanism, a previous paper ruled out the NMDA receptor pathway as a mediator of the effect of Aβ (3).

    While the studies published so far point towards different signaling mechanisms that could transduce or modulate the effect of Aβ on axonal transport (e.g., involving NMDA receptors, protein kinase A [2], casein kinase 2 [5]), these may be part of a more complex pathway of regulation of axonal transport at various stages: motor recruitment to the cargo, motor activation, motor release from the cargo, some subtle effect on the cytoskeletal tracks, etc.. However, it is more and more evident that GSK3β is an important regulator of axonal transport that is targeted by Aβ treatment (this study and [2]).

    Many questions still await answers in future studies. Among these, we would like to point to the fact that most of the studies have used very high concentrations of Aβ to trigger an effect on axonal transport. At these concentrations the inhibition of transport is dramatic: the analyzed cargoes are essentially brought to a halt. Such an effect could certainly not be tolerated by neurons for extended periods of time. But are these concentrations attainable locally in the Alzheimer disease (AD) brain? What about smaller concentrations of Aβ, applied continuously or intermittently over extended periods of time? So far, it appears that Aβ disrupts axonal transport by acting not only from the extracellular space, but also when present within the neuron (5). Which of these experimental conditions is more relevant to the situation in the AD brain? Maybe both (7,8).

    Interestingly, in an apparent contradiction of the studies summarized above, a report by Zempel et al. at the recent ICAD 2010 did not find any significant effect on axonal transport upon treatment of cultured neurons with Aβ oligomers, although tau localization and phosphorylation, as well as the integrity of microtubules, were affected. These results clearly show the necessity of further studies addressing the effect of Aβ on axonal transport.

    We would like to end the comment by noting that the studies discussed above suggest that abnormal axonal transport is a consequence of the increased accumulation of oligomeric Aβ in AD, and thus it is not the initial cause of the neuronal pathology seen in this disease. Still, this is an open question that will be difficult to answer without more refined means to detect with high sensitivity very early changes in axonal transport in the AD brain (1).

    References:

    . Is abnormal axonal transport a cause, a contributing factor or a consequence of the neuronal pathology in Alzheimer's disease?. Future Neurol. 2009 Nov 1;4(6):761-773. PubMed.

    . Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons. J Neurosci. 2006 Oct 11;26(41):10480-7. PubMed.

    . Glutamate and amyloid beta-protein rapidly inhibit fast axonal transport in cultured rat hippocampal neurons by different mechanisms. J Neurosci. 2003 Oct 1;23(26):8967-77. PubMed.

    . Human amyloid-beta1-42 applied in vivo inhibits the fast axonal transport of proteins in the sciatic nerve of rat. Neurosci Lett. 2000 Jan 7;278(1-2):117-9. PubMed.

    . Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5907-12. PubMed.

    . Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12. PubMed.

    . Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci. 2007 Jul;8(7):499-509. PubMed.

    . Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci. 2004 Apr 7;24(14):3592-9. PubMed.

  4. I agree with the three previous commentators that the levels of Aβ used in these experiments are high. Then again, we have no idea what the Aβ content is in and around our neurons, or rather our synapses—the active ones that is—where Aβ is claimed to be produced! On the other hand, lesser Aβ levels can be anticipated to produce lesser, more graded rather than complete disruption of FAT, which would eventually fit the late onset and/or progressive nature of AD.

    I did not have the pleasure that Virgil and Zoia Muresan had in attending ICAD Honolulu, and missed, therefore, the presentation by Zempel et al., but I would love to see their effects on tau! The raised—or renewed—controversy on whether Aβ affects FAT or not has been around for quite some time. My take on that issue is that the outcome of such in vitro studies depends on experimental conditions.

    Regarding the role or contribution of GSK3, I remain very puzzled, c.q. hungry, because the Decker paper does lift the lid off the pot but does not look inside for what is cooking.

    I agree with Stefan Kins that kinesin could, even should, have been looked at—regarding Morfini et al., 2002—while other pathogenic targets come to mind—and why not tau?

    Also, the citing of Rui et al. (2006) in the Decker paper, and by the Muresans (reference 2), does not help us to understand the contribution of GSK3β to FAT. Clearly, only the SB-compound is a specific GSK3 inhibitor, while one wonders about the low concentration of Li+ used (1 mM) and about the efficacy of valproic acid as a GSK3 inhibitor.

    I agree with Elliott Mufson that axonal transport is an important issue, independent of whether Aβ is the instigator, or tau, but dendritic transport is, at least, or even more, interesting! Evidently, it is not the cause of AD, but the cause of important collateral damage.

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