. Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 2008 Jun 26;58(6):871-83. PubMed.

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  1. A number of previous reports linked FAD-causing mutations in presenilins with abnormal endoplasmic reticulum (ER) Ca2+ signaling (1-3). Biochemical and functional interactions have been previously uncovered between presenilins and intracellular Ca2+ channels. Presenilin-2 has been previously reported to associate with inositol (1,4,5) trisphosphate receptor (InsP3R) and to enhance InsP3R activity (4). Presenilins were suggested to modulate ryanodine receptor (RyanR) gating by direct interactions (5) or via RyanR modulator sorcin (6). The new study by King-Ho Cheung at al. suggests that PS1-M146V and PS2-N141I FAD mutant presenilins specifically sensitize InsP3R1 to activation by InsP3. The effect of mutant presenilins on InsP3R1 sensitivity to InsP3 is very similar to the modulation of InsP3R1 by mutant Huntingtin that our group previously described (7).

    The results raise a question about the mechanism responsible for potentiation of intracellular Ca2+ release in PS-FAD expressing cells. One potential explanation is sensitization of InsP3R1 to low InsP3 concentrations as described. Another explanation is “overfilled ER Ca2+ stores” due to impaired “ER Ca2+ leak function” of PS1-M146V and PS2-N141I mutant presenilins as our group previously suggested (8,9). Stutzmann at al. previously performed detailed characterization of InsP3-evoked Ca2+ responses in hippocampal neurons from the PS1-M146V knock-in mouse model (10). Based on careful analysis of InsP3-evoked Ca2+ responses, those authors concluded that InsP3-induced Ca2+ responses were potentiated at all InsP3 concentrations tested. Stutzmann at al. further found that PS1-M146V and non-transgenic neurons displayed similar threshold sensitivity of Ca2+ release to low levels of InsP3. These results are consistent with the idea of “overfilled ER Ca2+ stores,” but not with the “InsP3R1 sensitization” model proposed by King-Ho Cheung et al. Recent data from Stutzmann at al. also indicate that RyanR-mediated Ca2+ release is also significantly enhanced in PS1-M146V KI neurons (11). These findings can be explained by an increase in RyanR expression level (as the authors suggested) or may also be due to “overfilled ER Ca2+ stores.”

    A number of groups reported Ca2+ signaling abnormalities in cells from PS1 and/or PS2 knockout mouse (8,12-15). Most of the data shown by King-Ho Cheung et al. suggest that wild-type PS1 and PS2 have very little or no effect on InsP3R1 gating and cannot explain the abnormal Ca2+ signals reported for PS knockout cells. In contrast, we were able to explain Ca2+ signaling defects observed in PS1/2 DKO cells as a result of loss of ER Ca2+ leak function and to rescue the Ca2+ phenotype of PS DKO cells by overexpressing wild-type PS1 or PS2 (8).

    Obviously, future studies will be needed to better understand the mechanisms responsible for ER Ca2+ signaling abnormalities observed in PS-FAD expressing cells. In particular, it will be very interesting to find out if other PS1-FAD mutants which caused “loss of ER Ca2+ leak function” in our experiments (L166P, A246E, E273A, G384A, and P436Q) (9) also potentiated sensitivity of InsP3R to InsP3 as Cheung at al. observed for PS1-M146V and PS2-N141I mutants. We may find that presenilins are connected with ER Ca2+ signaling at several levels, by acting both as ER Ca2+ leak channels and by modulating activity of intracellular ER Ca2+ channels (InsP3R and RyanR).

    References:

    . Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nat Rev Neurosci. 2002 Nov;3(11):862-72. PubMed.

    . Calcium dysregulation in Alzheimer's disease: recent advances gained from genetically modified animals. Cell Calcium. 2005 Sep-Oct;38(3-4):427-37. PubMed.

    . The pathogenesis of Alzheimers disease is it a lifelong "calciumopathy"?. Neuroscientist. 2007 Oct;13(5):546-59. PubMed.

    . The presenilin-2 loop peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis. J Biol Chem. 2006 Jun 16;281(24):16649-55. PubMed.

    . The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity. Int J Biochem Cell Biol. 2008;40(1):84-97. PubMed.

    . Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor. J Biol Chem. 2000 May 12;275(19):14440-5. PubMed.

    . Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron. 2003 Jul 17;39(2):227-39. PubMed.

    . Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell. 2006 Sep 8;126(5):981-93. 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.

    . Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer's-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci. 2004 Jan 14;24(2):508-13. 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.

    . Presenilin-mediated modulation of capacitative calcium entry. Neuron. 2000 Sep;27(3):561-72. PubMed.

    . Capacitative calcium entry induces hippocampal long term potentiation in the absence of presenilin-1. J Biol Chem. 2003 Nov 7;278(45):44393-9. PubMed.

    . Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein. J Biol Chem. 2003 Jan 24;278(4):2484-9. PubMed.

    . Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling. FASEB J. 2005 Dec;19(14):2069-71. PubMed.

  2. The study by Foskett (Cheung et al.) provides a novel and detailed study of the mechanisms by which mutant PS increases ER calcium release—a long-standing question which has generated much hand-waving. Only a few technically qualified labs are attempting to tackle this conundrum, and with this group’s experience in single channel recordings of IP3R and major contributions to IP3 channel biophysics (Foskett et al., 2007), setting their sights on calcium dysregulation mechanisms in AD is a welcome expansion. By recording properties of single IP3 channels, the authors showed that coexpression with mutant PS alters the channel gating properties and increases the open probability of the IP3R, i.e., mutant PS locks the IP3 channel open for longer periods and thereby releases more calcium from the ER into the cytosol. This is most profound at low IP3 concentrations, such that a threshold IP3-evoked calcium response is observed with wt PS coexpression, but a large ER calcium response is evoked with mutant PS. Importantly, this IP3R sensitization was demonstrated in neurons as well as other model cells.

    In this study, a consequence of mutant presenilin’s sensitization of the IP3R is an overall reduction in ER calcium content. This raises some interesting conversations since it is in opposition to assumptions that the increased ER calcium release is due to over-filled stores. Despite my initial agreements with the latter, I am presently unclear about the steady-state ER calcium store levels in mutant PS expressing neurons. For example, we have found that blocking the ryanodine receptor (RyR) will normalize the exaggerated IP3-evoked calcium response—this is not consistent with overfilled ER stores (Stutzmann et al., 2006). However, in brain slice preparations from adult mice, it is difficult to access intracellular organelles and measure discrete calcium levels from within, as Foskett’s group had done. I do suspect observed differences in calcium levels and underlying mechanisms may, in part, be due to different models used—as mentioned in the related commentary, neurons are funny creatures with distinct calcium signaling requirements.

    Historically, the IP3R was considered the guilty party underlying the PS-mediated calcium dysregulation. Yet, several recent studies have shifted culpability from the IP3R to the RyR (Stutzmann et al., 2006; Smith et al., 2005). Although the RyR is not addressed in this Foskett study, and therefore a part of the puzzle is missing, it is known that IP3- evoked calcium release can modulate RyR responses and vice versa, and it is possible the mutant PS can similarly alter RyR gating properties. I believe a resolution is in there somewhere, and more detailed studies disentangling these channels are underway in my lab (stay tuned…).

    A finding that is consistent with the past and present literature is that IP3R and mutant PS interactions stimulate β amyloid processing. Mutant PS increases the Aβ42:Aβ40 ratio, and the important finding here is that this ratio shift is ameliorated in IP3R KO cells. This new finding nicely ties together mutant PS, IP3R, and APP processing: rather than mutant PS exerting two independent and parallel pathogenic effects (as previously suspected), a new possibility is presented in which the IP3R and APP processing are coupled, and mutant PS is interfering with an existing process. Notably, the Dreses-Werringloer study also finds a positive link between expression of the AD-linked polymorphism of the CALHM1 calcium channel and pathogenic APP processing, yet the polymorphism reduces calcium permeability of the channel (see related comment below). A potential resolution is that this novel channel serves as an ER leak channel, and therefore, the polymorphism impairs regulatory calcium exit from the ER lumen, resulting in increased store levels. This would generate a condition similar to that proposed in Tu et al., where mutant PS is impaired in its proposed leak channel function, resulting in increased store levels. Here again we enter the ER-calcium level debate, which is worthy of another review.

    These two calcium channel studies each provide a detailed, mechanistic approach for translating how gene mutations linked to AD can directly alter calcium channel function. This in itself is a welcome and much-needed approach, even though the phenotypes do not align exactly. A take-away message is that the link between calcium dyshomeostasis and AD pathogenesis need not point to deficits in a single channel, but, may reflect the metabolic impact of coping long-term with intracellular calcium dyshomeostasis.

    References:

    . Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev. 2007 Apr;87(2):593-658. 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.

    . Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer's disease. J Neurochem. 2005 Sep;94(6):1711-8. PubMed.

    . Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell. 2006 Sep 8;126(5):981-93. PubMed.