. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci. 2004 Nov;7(11):1181-3. PubMed.

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  1. This is a very interesting paper that adds to our understanding of the in-vivo biology of plaques, and it would be interesting to add further nuances to these insights by comparing the effects of diffuse versus neuritic plaques on the integrity of dendrites, since in an earlier study >10 years ago of diffuse plaques in human cerebellum (Li et al., 1994), we did not see evidence of plaque toxicity on Purkinje cell dendrites, but in addition to the fact that we restricted our observations to diffuse plaques, the methods we used were diffrent from those reported here by Tsai et al. Nonetheless, given the many known differences between diffuse and neuritic plaques, it would be important to understand if these differences also extend to the relative toxic potential of each of these plaque types, since diffuse plaques may harbor components that mitigate toxicity which are not found in neuritic plaques.

    View all comments by John Trojanowski
  2. In studies quite similar to those of Tsai et al., we did not see clear associations between amyloid plaques and the loss of dendritic spines (Moolman et al., 2004), though we did a observe a similar (approximately 50 percent) loss of spines in two different mouse models of AD at 11 months of age and a suggestion of loss at eight months of age. We have tended toward the view that it is soluble Aβ rather than Aβ that is organized into plaques that are responsible for alterations in synaptic plasticity. It is certainly possible that soluble Aβ is higher in the region of the plaque, and that would reconcile the observations. Floyd Bloom's lab has pointed to dendritic alterations very early in the life of another AD model mouse prior to significant plaque formation, but did not specifically look at spines (Wu et al., 2004).

    View all comments by Michael Shelanski
  3. These interesting papers by Tsai et al. and Moolman et al. further support the idea that neuronal processes are important sites of damage during AD pathogenesis. A major question, of course, is why are processes being damaged? Is there any damage prior to plaques? Both papers consider the possibility that increases in levels of soluble Aβ may be important. In addition, increasing evidence supports a role for intraneuronal Aβ accumulation in the degeneration of processes (for example, see Wirths et al., 2004, for a current review).

    View all comments by Gunnar Gouras
  4. I think the data in the Gan paper is quite beautiful. I especially liked the time-lapse results in Figure 2 using the transcranial approach. I think their findings nicely extend previous work that showed an association between abnormalities of dendrites and the proximity of plaques. I also am especially interested in the effects on the rate of spine formation and elimination, since I think a lot of the symptoms in AD probably arise from synaptic dysfunction rather than neuronal death.

    The work also raises a lot of intriguing questions. Is the effect they see really due to the amyloid in the plaque or is the plaque a major source for more toxic diffusible forms of Aβ whose concentration is therefore high around the plaque? Either model would explain the close relationship between the existence of dendritic abnormalities and their distance from the plaque. However, the answer would have big implications for developing therapeutic strategies. To answer the question, they would need some way to simultaneously visualize both forms of Aβ (plaque and diffusible) in living tissue. Another question is whether the plaque-associated abnormalities are a major or minor contributor to the overall behavioral phenotype—that one is a lot tougher.

    View all comments by Steven Finkbeiner
  5. I agree with the previous comments in that this paper provides elegant confirmation of earlier research on how plaques impact neural structure. In addition, they show a substantial increase in the turnover of spines and dystrophic axon terminals, indicating that abnormal plasticity is occurring. Whether this is caused by amyloid or other diffusible molecules such as growth factors, this abnormality is likely to strain the capacity to produce, synchronize, and transport plasticity-related proteins—in addition to the obvious negative effects of the structural changes. It will, thus, also be interesting to see how this relates to the function of affected neural systems.

    View all comments by Michael Calhoun
  6. This paper shows a nice view of the neurodegeneration of dendritic spines, but I am not really sure how it relates plaques to mophological changes. In this experiment we would need examine the role of the glia cells, and their contribution to plaque formation. I wonder if it is possible to see the same effect without glial cells?

    View all comments by Jorge Parodi

This paper appears in the following:

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