. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2012 May 29;109(22):8740-5. Epub 2012 May 16 PubMed.


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  1. These data provide some of the strongest support to date of the hypothesis that Aβ species—likely soluble forms of Aβ— interfere with synaptic function in vivo and are associated with a hyperactive circuit within the hippocampus. Further investigations of this animal model will likely provide important additional information about the mechanisms of aberrant physiology in the context of pre-plaque Aβ-related hippocampal dysfunction. It would be particularly interesting to investigate whether the hyperactivation further promotes Aβ release and possibly fibrillar accumulation in a vicious cycle. In addition, these findings further support the potential value of functional MRI markers of hippocampal hyperactivation in living humans with MCI as indicators of circuit dysfunction, and suggest that hippocampal hyperactivation should be investigated as a possible early marker of therapeutic response in clinical trials in which Aβ-modifying drugs are given to humans.

  2. In the past weeks, two studies using APPxPS1 transgenic animals describe abnormal calcium homeostasis as a potential early event in asymptomatic pre-plaque mice. Despite remarkable technical skills displayed by both teams, there studies might suffer from the same experimental confound.

    The first report, by Arthur Konnerth’s group (Busche et al., 2012), is a follow-up study of previous work from the same group (Busche et al., 2008), which suggested the presence of clusters of hyperactive neurons near amyloid plaques in the bigenic APP23xPS45 mouse model. Using the same APP transgenic mice, this new article documents an impressive use of two-photon microscopy to investigate potential dysregulation of calcium signaling in hippocampal neurons in vivo. The authors report that, not only does apparent elevation of calcium signaling occur around plaques, but also that it takes place in younger, pre-plaque animals. Following the demonstration that spontaneous Ca2+ transients correspond to neuronal activity, Konnerth’s group then acutely applied the γ-secretase inhibitor LY-411575 to test whether Aβ was responsible for the observed effect. One single dose of the pharmacological agent reduced Aβ production and partly abolished neuronal hyperactivity in hippocampal neurons. The authors next applied synthetic Aβ dimers (AβS26C) at 100 nM for 30 seconds to hippocampal neurons in non-transgenic mice and observed a marked increase in Ca2+ transients. Busche and coworkers then concluded that soluble Aβ were responsible for early hippocampal hyperactivity seen in APP transgenic mice.

    While the technique is remarkable and the demonstration that short-term application of synthetic Aβ dimers at concentrations possibly relevant to disease triggers abnormal rises in Ca2+ signaling is convincing, I have some concerns about the overall conclusion.

    First, the authors used a mouse line (here, and in their previous work) that not only expresses a mutant form of human APP (APPswe) driven by the Thy1 promoter, but it also expresses a mutant form of PS1 (i.e., PS1G384A). Since the mid-1990s (Ito et al., 1994), numerous lines of evidence suggest that PS1 is involved in regulating Ca2+ homeostasis (see, for review, Green and LaFerla, 2008; Ho and Shen, 2011), and that FAD PS mutations cause abnormal Ca2+ signaling. More recently, the De Strooper and Bezprozvanny groups showed that several FAD PS1 mutations are loss-of-function mutations affecting ER Ca2+ leak activity (Nelson et al., 2007). The G384A PS1 mutant that Busche and coworkers used leads to greater than a twofold increase in ER Ca2+ concentration. This complicates interpretation. PS45 (Thy1-PS1G384A) and APP23 mice would be appropriate controls for PS-specific effects and for the γ-secretase inhibitor experiments that suggested calcium increases were due to APP/Aβ overexpression.

    Second, the use of topically applied synthetic Aβ dimers in mice is somewhat counterintuitive. While Ca2+ signaling is altered in 1.5-month-old, plaque-free APP23xPS45 animals, no data are provided to determine what forms of soluble Aβ species are present in these mice. Considering that levels of soluble Aβ dimers parallel the formation of plaques (Larson and Lesne, 2012), and taking into account that young (1.5- to 1.8-month-old) bigenic mice do not display amyloid plaques (Supplementary Fig. S1), it is difficult to justify the use of synthetic dimers in this paradigm. In my opinion, it would have been more interesting to know what is present in the young bigenic mice and to try to purify and apply it to their open cranium preparation to demonstrate what is causing this putative increase in Ca2+ signaling.

    Overall, I am puzzled as to how the authors conclude that the elevation of Ca2+ signaling (and by proxy, neuronal activity) observed in APP23xPS45 neurons is due to soluble Aβ.

    The second study, by Chakroborty and colleagues, also deals with abnormal calcium signaling in the 3xTg AD mouse model created by Frank LaFerla’s group. These animals express mutant forms of APP (APPswe), human tau (TauP301L), and presenilin-1 (PS1M146V-KI) (Oddo et al., 2003). In particular, the authors try to address the origin of altered Ca2+ homeostasis that may underlie synaptic depression. In presymptomatic ~1.5-month-old 3xTg-AD, the upregulation of ryanodine receptor (RyR) activity appears counterbalanced by increases in presynaptic spontaneous vesicle release, altered probability of vesicle release, and upregulated postsynaptic SK channel activity. The authors conclude that ER Ca2+ disruptions due to modulation of RyR signaling are associated with PS1 mutations, rather than tau or Aβ. While this work reveals new details in dysregulation of Ca2+ homeostasis in 3xTg-AD mice, one would expect to compare 3xTg-AD with APPTau, PS1M164V-KI, and non-transgenic littermates, especially since this group previously showed that both 3xTg-AD and PS1M164V-KI mice display a similar “calciumopathy” (Stutzmann et al., 2006).

    Altogether, my personal interpretation is that the new results presented here suggest that responses to RyR modulation could be solely due to mutant PS1 expression, or to some effect of human APP/Aβ/Tau expression on PS1M146V-induced calcium alterations.

    In summary, I think it is extremely important to distinguish the effects of mutant PS1 on Ca2+ signaling from changes triggered by human Aβ or tau species in APPxPS1 mice in order to attribute causality and consequence between the molecules involved.


    . Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2012 May 29;109(22):8740-5. Epub 2012 May 16 PubMed.

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

    . Linking calcium to Abeta and Alzheimer's disease. Neuron. 2008 Jul 31;59(2):190-4. PubMed.

    . Presenilins in synaptic function and disease. Trends Mol Med. 2011 Nov;17(11):617-24. PubMed.

    . Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):534-8. PubMed.

    . Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Epub 2007 Apr 12 PubMed.

    . Soluble Aβ oligomer production and toxicity. J Neurochem. 2012 Jan;120 Suppl 1:125-39. PubMed.

    . Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer's disease mice. J Neurosci. 2012 Jun 13;32(24):8341-53. 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.

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