. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science. 2008 Sep 19;321(5896):1686-9. PubMed.


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  1. This is a very interesting article. From our perspective, there are several important points: first, it highlights a plaque-specific alteration of neural function, but emphasizes that this occurs in the vicinity around plaques, suggesting a halo effect of a potentially soluble mediator, which is critical to alter activity. Second, it uses an alternative technical strategy to the one utilized by my colleague Brian Bacskai (Kuchibhotla et al., 2008), which used gene transfer of a genetically encoded Ca2+ reporter to observe neurites near plaques, as opposed to loading of an AM molecular dye to monitor neuronal perikarya, to come to a similar conclusion—that neurons in the vicinity of plaques have a profound dyshomeostasis of calcium regulation. Third, that neural systems are markedly disrupted by the presence of plaques, with functional alterations leading to both increased and decreased activity affecting a large percentage of neurons. This neural system collapse provides a plausible biological underpinning for the cognitive impairment in AD.


    . Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron. 2008 Jul 31;59(2):214-25. PubMed.

    View all comments by Bradley Hyman
  2. This is a great paper that confirms our and others’ work that senile plaques are a focal source of toxicity. The implications of the hyperactivity are unknown; however, it is apparent that a disruption to the normal network activity in the brain is obvious. These data are in line with our own measurements of altered resting calcium concentration in neurons in animals with senile plaques and suggest that a more detailed examination of the calcium hypothesis of AD is warranted.

    We have not looked at spontaneous activity of neuronal calcium signaling in the brain, so we cannot confirm these results as yet, but it would be interesting to probe whether these observations share similarities to physiologically relevant evoked responses.

    In sum, this paper confirms that calcium imaging as an indicator of neuronal activity, and calcium imaging as an indicator of dyshomeostasis of calcium concentration, is an important future direction for our understanding of the disruption of the cellular and network disruption of neuronal signaling in AD.

    View all comments by Brian Bacskai
  3. This is a very interesting paper and consistent with our results from primary hippocampal neurons derived from APPswe transgenic rats. We have recently shown that modest overexpression of APPswe results in increased frequency but unaltered amplitude of spontaneous calcium oscillations in these transgenic neurons (Kloskowska et al., 2008a). Furthermore, we found that the baseline of calcium oscillations was significantly higher than in control neurons (Kloskowska et al., 2008b). Thus, recent data implies that the relationship between Aβ and neuronal activity is more complex than has been thought.


    . APPswe mutation increases the frequency of spontaneous Ca2+-oscillations in rat hippocampal neurons. Neurosci Lett. 2008 May 9;436(2):250-4. PubMed.

    . The APP670/671 mutation alters calcium signaling and response to hyperosmotic stress in rat primary hippocampal neurons. Neurosci Lett. 2008 Oct 31;444(3):275-9. PubMed.

    View all comments by Ewa Kloskowska
  4. A very timely article is presented here by Bushe et al., demonstrating a relationship between amyloid plaques and intraneuronal calcium signaling dysregulation using 2-photon imaging techniques in vivo. The authors found diverging populations of neurons in plaque-expressing APPxPS45 mice relative to controls, in that one group decreased calcium transient activity while another “hyperactive” group in close proximity to plaques increased frequency of calcium transients. Reduction in inhibitory synaptic tone resulting from impaired GABAergic transmission is provided as the mechanism.

    Overall, this technically demanding study adds to the existing literature demonstrating that neuronal calcium alterations are an integral component of AD pathology—whether through PS mutations, extracellular plaques, or other AD-linked pathways. This is a new view on how AD pathology can affect neuronal signaling, and will hopefully spin off several follow-up studies.

    What I do find lacking (perhaps will be addressed in follow-up?) is 1) a mechanism for why GABAergic neurons may be more vulnerable to plaque pathology, since they are loaded with calcium buffers and tend to be less susceptible to excitotoxicity, and 2) a means to determine how/if the “quiet” cells are GABAergic, and if the hyperactive cells are pyramidals or another non-inhibitory other subtype.

    Much of cortex contains a granular layer (L. IV) containing largely interneurons, with the exception of the prefrontal region, and it is not clear where in frontal cortex these recordings are taking place. This may change the negative feedback circuit anatomy and have some implications here. Since the pharmacology examines local transmitter effects, it is difficult to make assumptions about the source. The possible role of intracellular calcium waves, triggered by glutamatergic activity but generated by intracellular calcium sources, is also a possible mechanism but is not yet addressed in these studies.

    Recently, similar approaches were used in a study from Brian Bacskai's group (Kuchibhotla et al., 2008), and although the general idea is also that calcium levels are disrupted in neurons close to plaques, some significant differences in the details are evident. Although temporal domains of calcium signaling were not the primary focus, it does not appear that calcium oscillations were observed in their cortical neurons. Rather, they observed increases in steady-state calcium levels in neuronal processes close to plaques. Similar to our findings, neurons from control mice do regulate their calcium levels quite well over time (Stutzmann et al., 2006), as do neurons from the AD mice sufficiently removed from plaque deposits. Although mechanisms for this increased steady-state calcium load aren't investigated, it does not appear synaptic/activity-dependent in nature. Granted, there are differences in the techniques and calcium indicator approaches used in the two studies, so as much as I'd like to avoid this euphemism...more studies are needed.


    . Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron. 2008 Jul 31;59(2):214-25. PubMed.

    . Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer's disease mice. J Neurosci. 2006 May 10;26(19):5180-9. PubMed.

  5. The increase in activity in some of the neurons near the amyloid plaques in the layer of cortical neurons is surprising, but it makes sense when it is framed, just as the authors did, in the “synaptic failure hypothesis.” This finding could very well be related to the observation that endocytosis of glutamate receptors is observed in certain animal models of AD. Dysfunction of Ca2+ kinetics is probably causing the calcium overload the authors mention (seen in another study).

    Would it be interesting to look specifically at which neurons are affected? Could it be that GABAergic neurons are being affected the most, and their dysfunction thereby resulting in an overall increase in excitation? The main question still to be answered is why is it that some of the cortical neurons decrease activity, while others increase neuronal activity? In the conclusion, the authors mention anatomical remodeling in synaptic inputs as a possible cause. This explanation, although plausible, does not clarify within which mechanism are the chemical signals from Aβ affecting the neurons. Could it be that defective neurogenesis is also occurring, adding to the changes in neuronal function?

    Interestingly, distance from the plaques seems to be the determining factor of whether increase or decrease in activity is seen (the mechanism AB uses to affect neurons could be similar to what is seen in neural development, where chemical gradients determine the “identity” of a cell). The fact that Aβ is the main factor in the hyperactivation of neurons close to the cortical layer 2/3 was strengthened by the results of the predisposing APP23xPS45 mice study. Unfortunately, the fact that these predisposing mice present normal cortical activity and Ca2+ function rules out the use of these biological markers in pharmacological studies for prevention of AD. However, because the APP mice do present behavioral deficits in the discriminatory water maze and the Y-maze, there may be a possibility that an in between age (between two months and six months) could serve as a model for testing of preventive drugs.

    View all comments by Karienn Montgomery

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