It’s not all about amyloid and tau. Amid a torrent of discoveries touting toxic clusters of each as pathological hallmarks of Alzheimer disease, other scientists have trod a less beaten path. They consider AD pathogenesis from a different, but not necessarily mutually exclusive, perspective—one that pins the blame on intraneuronal calcium dysregulation. Two papers published this week in Neuron and Cell give “Calcinists” reason for cheer, and may even begin to forge a more holistic AD hypothesis incorporating their doctrine along with those of Baptists and Tauists.

In the Neuron paper, scientists report how sophisticated electrophysiology techniques, along with biochemical and functional assays, suggest a new mechanism by which mutant presenilins (PS1 and PS2)—two of three known genes linked to early-onset AD—can cause intraneuronal calcium signaling to run amok. Led by J. Kevin Foskett of the University of Pennsylvania, Philadelphia, the researchers propose that mutant PS1 and PS2 boost calcium outflow from the ER through interactions with the inositol 1,4,5-trisphosphate receptor (InsP3R) calcium release channel, and that these calcium perturbations are linked with enhanced Aβ production.

Writing in Cell, researchers led by Philippe Marambaud at the Feinstein Institute for Medical Research in Manhasset, New York, identified and characterized a novel gene, CALHM1 (calcium homeostasis modulator 1), encoding a transmembrane glycoprotein with calcium channel-like properties. The researchers also found an AD-linked CALHM1 polymorphism that increased Aβ production by disturbing CALHM1-mediated calcium permeability in transfected cells. Based on these findings, they propose that CALHM1 controls Aβ levels and that variants of this gene may increase susceptibility to late-onset AD.

“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,” wrote Grace Stutzmann of Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, in an e-mail to ARF. In a recent review, Stutzmann discusses evidence for why AD pathogenesis can be seen as a lifelong “Calciumopathy” (see Stutzmann, 2007).

A large number of studies using various experimental systems—including cells from AD patients, cultured neuronal and non-neuronal cells expressing mutant PS proteins, and primary brain neurons from mutant PS transgenic mice—have established the connection between mutant presenilins and aberrant intracellular calcium regulation. To get a handle on the mechanism behind these long-standing observations, Foskett and collaborators applied a unique patch-clamp technique he developed years ago for recording ion channel activity at the single-molecule level.

First author King-Ho Cheung and colleagues did one set of recordings in Sf9 cells (an insect line expressing the InsP3R isoform most closely related and functionally similar to the type 1 channel in mammalian brain) infected with wild-type or mutant PS1 (M146L) baculovirus. The team also rigged up chicken DT40 cells (which express native InsP3R) that stably express the same PS1 proteins. In both systems, expression of mutant PS1 exerted powerful stimulatory effects on InsP3R gating activity (i.e., higher open probability and mean open time, lower mean closed time) at saturating and subsaturating IP3 levels. The researchers saw a similar trend in Sf9 cells expressing mutant PS2 (N141I) and, importantly, in mutant PS1-transfected cortical neurons from mouse brain. That these effects were seen in ER membrane patches from isolated nuclei suggested a biochemical association between PS and InsP3R—which indeed was shown, for wild-type and mutant forms of PS1 and PS2, in immunoprecipitates of Sf9 lysates. The wild-type PS proteins had some effects on InsP3R activity as well. PS1 enhanced the channel’s mean open time, though to a lesser extent than mutant PS1, and it increased the mean closed time. PS2 also increased both mean closed and open times.

To test whether the InsP3R-PS interaction had AD-relevant functional consequences, coauthors Diana Shineman and Virginia Lee, also at the University of Pennsylvania, evaluated Aβ production in APP-transfected DT40 cells that also expressed wild-type or mutant PS1. Mutant PS1 increased Aβ40 and Aβ42 levels by about two- and threefold, respectively, relative to control cells. But when the researchers made similar measurements in InsP3R-deficient cells, they saw no such Aβ enhancement by mutant PS1. These findings suggest that the changes in APP processing by mutant PS1 depend on its interactions with InsP3R.

In a phone conversation with this reporter, Foskett noted that his team had initially tested whether the presenilin proteins themselves behaved as ion channels. This idea was proposed in an earlier study by Ilya Bezprozvanny and colleagues at the University of Texas Southwestern Medical Center, Dallas (see ARF related news story). “Our preliminary experiments couldn’t find any evidence for that,” Foskett said.

For the CALHM1 channel connection, lead author Ute Dreses-Werringloer and colleagues used the Alzgene database and a bioinformatics-based tool developed by coauthor Fabien Campagne (Skrabanek and Campagne, 2001) to look for potential late-onset AD (LOAD) risk factors among genes expressed specifically in the hippocampus. Their search pulled out CALHM1, an as yet uncharacterized gene encoding a glycoprotein expressed primarily in adult brain and localized to the ER and plasma membrane. The gene shares sequence similarities with the ion selectivity filter of the N-methyl-D-aspartate (NMDA) receptor, the researchers found. In experiments with CALHM1-transfected neuronal cell lines, the scientists showed that CALHM1 forms multimers and controls cytosolic calcium concentration. Foskett was also a coauthor in this work, as his group did electrophysiology studies that helped finalize CALHM1’s identification as a calcium channel component.

In genetic screens of more than 3,400 subjects in five independent European cohorts, coauthor Jean-Charles Lambert of the Institut Pasteur de Lille, France, and colleagues determined that the frequency of a CALHM1 polymorphism was significantly higher (allele-specific odds ratio = 1.44) in AD cases.

The researchers showed that in APP-transfected cells this polymorphism (P86L) reduced cytosolic calcium levels, presumably by interfering with CALHM1-mediated calcium permeability, and increased Aβ production about twofold.

“Both papers have gone out of their way to pay homage to the amyloid hypothesis in an effort to gain legitimacy for their findings,” wrote Zaven Khachaturian in an e-mail to ARF. Khachaturian is president and CEO of the Lou Ruvo Brain Institute in Las Vegas, Nevada. As a former director of Alzheimer’s research at the National Institutes of Health, he first proposed the calcium hypothesis for AD and brain aging in the early 1980s (for the most up-to-date version, see Khachaturian, 1994). “It is interesting that both CALHM1 and PS1/PS2 mutations affect amyloid production, which in fact might be a crucial step in neurodegeneration,” Khachaturian wrote. “However, it is equally likely that the disruption in cytosolic calcium concentration in and of itself might be the culprit—without the amyloid.”

In the Calcinists’ view, intraneuronal calcium dysregulation could arise in a variety of ways, many through the normal aging process. The calcium buildup could give rise to numerous possible scenarios, Khachaturian suggested—microtubule disassembly, axoplasmic flow disruptions, activation of proteases (perhaps those that cleave transmembrane proteins such as APP), to name a few. “If the excessive amyloid is playing a toxic role, it’s doing that in addition to the underlying problems with calcium,” Khachaturian said in a phone interview.

Foskett told ARF his group has looked past amyloid and begun to examine their mutant PS-expressing cells for more general effects of calcium dysregulation—for example, generation of reactive oxygen species and activation of calcium-regulated transcription factors. “This is turning out to be a remarkable story I can’t talk about right now,” he said.

Foskett and colleagues are also starting to look for the PS/InsP3R-induced phenotypes in AD transgenic mice. One approach is to look at genes upregulated as a result of exaggerated calcium signaling in their cell culture models, and then ask whether the gene expression profile looks similar in AD mouse brains. “It’s a little bit indirect,” he said, “but it’s a way of asking whether what we’ve been doing in vitro is corroborated in vivo.”

For their part, Marambaud and colleagues are generating a CALHM1 knockout mouse. They plan to cross these animals with APP transgenic mice to see if CALHM1 deficiency boosts Aβ deposition and promotes cognitive decline, Marambaud told ARF.

As Bezprozvanny sees it, the CALHM1 and PS/InsP3R findings are just the tip of the AD-calcium iceberg. “There is no doubt future studies will uncover additional connections between calcium signaling and amyloid processing,” he wrote in an e-mail to ARF. “It may well be that the ‘calcium hypothesis of AD’ and the ‘amyloid hypothesis of AD’ are much more closely related than it initially appeared.”—Esther Landhuis.

References:
Cheung K-H, Shineman D, Mueller M, Cárdenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee V M-Y, Foskett JK. Mechanism of Ca2+ Disruption in Alzheimer’s Disease by Presenilin Regulation of InsP3 Receptor Channel Gating. Neuron. 26 June 2008;58:871-883. Abstract

Dreses-Werringloer U, Lambert J-C, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P. A Polymorphism in CAHLM1 Influences Ca2+ Homeostasis, Abeta Levels, and Alzheimer’s Disease Risk. Cell. 27 June 2008;133:1149-1161. Abstract

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  1. It is certainly exciting that calcium signaling dysregulations and their relationship to AD are being examined in novel ways. The recent study by Dreses-Werringloer et al. appears to link some of the leading, but functionally disparate, hypotheses of AD, namely the amyloid cascade line of research and the role of calcium dysregulation in AD pathogenesis. Here, they have uncovered a novel gene (CALHM1) encoding a transmembrane protein with calcium channel-like properties which, in addition to selectively passing calcium, can modify APP processing as well.

    There are several interesting findings relevant for calcium channel biophysicists as well as AD researchers imbedded in this study. For example, the localization of the protein product is intriguing, since it’s predominantly in the ER membrane but also found in the plasma membrane of some cells. From the information provided, it is unclear if the CALHM1 channel is found in the plasma membrane of adult neurons, or exclusively in the ER, which could lead to considerably different implications for AD disease mechanisms. The channel’s intended function is also an interesting mystery. Based on the assays performed in this study, it appears to act as a store-operated calcium channel (SOCC) on the plasma membrane, but is not blocked by conventional SOCC blockers. Given its localization in the ER, its role there is of particular interest, since it appears functionally independent of presenilin, or the IP3R or RyR calcium channels—all resident in the ER membrane. I do wonder about a possible role of the CALHM1 channel as an ER leak channel (with an acknowledgment to Ilya Bezprozvanny and his studies identifying presenilin as a leak channel) and, therefore, it would be interesting to see effects of the CALHM1 polymorphism on ER calcium leak by blocking sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pumps with thapsigargin. It is with great interest and appreciation that “Calcinists” follow these and related studies, but I am presently left with a few more questions regarding how this study fits into the existing body of knowledge about calcium dysregulation in AD. In the present AD literature (including reviews cited in this study), calcium levels/release/signaling is increased/upregulated/exaggerated with PS mutations, ApoE4 alleles, or Aβ oligomers/tau pathology (see Stutzmann, 2007; LaFerla, 2002, for reviews), yet the AD-linked polymorphisms in CALHM1 reduced calcium permeability and cytosolic calcium levels. In addition, the reduced calcium influx occurred in parallel with increased production of pathogenic APP fragments. This is inconsistent with the expected relationship between calcium levels and β amyloid production, although more complex feedback or homeostatic mechanisms may be activated that were not observed yet. Another question raised is the temporal relationship between the polymorphism expression (since birth) and presence of plaques (decades later). In these studies, increased Aβ is observed days after transfection, but how that may translate into the human condition requires a different timeline. Despite these and other interesting questions, this study provides a novel opportunity to re-examine the role of calcium dysregulation and AD pathogenesis in an entirely new light.

    View all comments by Grace Stutzmann
  2. 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).

    View all comments by Ilya Bezprozvanny
  3. 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.

    View all comments by Grace Stutzmann
  4. Amyloid-calcium Connection Is Getting More Intimate
    The recent paper by Ute Dreses-Werringloer and colleagues provides a very interesting and unexpected connection between Ca2+ signaling and amyloid. By focusing on LOAD locus 10q24.33, the authors identified a hippocampal-specific transcript that appears to encode a novel ion channel. In a series of functional experiments, they demonstrated that expression of this transcript in a heterologous system supports Na+ and Ca2+ influx. They called this new gene calcium homeostasis modulator 1 (CALHM1). By direct sequencing of the CALHM1 genomic region from AD cases and age-matched controls, the authors discovered that a point mutation (P86L) in CALHM1 has a significant association with an earlier age of AD onset. In functional experiments they demonstrated that the P86L mutation reduces permeability of CALHM1 for Ca2+, consistent with a partial loss of function. By performing experiments with cells stably expressing the APP-Swedish mutant, the authors found that Ca2+ influx via CALHM1 stimulated α-secretase cleavage of APP and reduced the amounts of Aβ40 and Aβ42 produced in these cells. In contrast, expression of P86L mutant of CALHM1 had no effect on production of Aβ40 and Aβ42.

    These are very intriguing and exciting findings that raise a number of questions. In their experiments the authors used a “Ca2+ addback” protocol, which enabled them to unmask activity of CALHM1 channels. But in physiological situations, neurons are exposed to constant extracellular Ca2+ levels. The CALHM1 channel appears to be constitutively active and does not require membrane depolarization (as voltage-gated Ca2+ channels do), ligand (as NMDA receptors do), or store depletion (as SOC and TRP channels do) for activation. These properties suggest that the CALHM1 channel acts as a plasma membrane cation leak channel, which supports passive influx of Na2+ and Ca2+ ions into hippocampal neurons. One can expect that a channel like this would be involved in setting membrane resting potential, input resistance, spontaneous electrical activity of hippocampal neurons (due to Na2+ permeability), and also in controlling cytosolic Ca2+ homeostasis (due to Ca2+ permeability). The LOAD-associated P86L mutation appears to affect Ca2+ and not Na+ permeability of these channels, so from these data it appears that the Ca2+ channel function is more relevant for AD.

    A number of previous reports linked FAD-causing mutations in presenilins with abnormal endoplasmic reticulum (ER) Ca2+ signaling (1,2). Our group proposed that presenilins function as “ER Ca2+ leak channels” that control passive Ca2+ flux across the ER membrane (3). We further found that many FAD-mutations cause complete loss of ER Ca2+ leak function of presenilins (3,4). The findings of Dreses-Werringloer et al. indicate that CALHM1 acts as a “plasma membrane Ca2+ leak channel” and that partial loss of function mutation P86L is associated with earlier onset of AD. Coming from two different directions, both of these findings hint at a potential connection between neuronal Ca2+ homeostasis and pathogenesis of AD. Dreses-Werringloer et al. propose one specific mechanism that links CALHM1-mediated Ca2+ influx with stimulation of α-secretase cleavage of APP and corresponding reduction in levels of generated Aβ40 and Aβ42. On another hand, previous studies demonstrated that global intracellular Ca2+ increase can stimulate production of Aβ40 and Aβ42 (5,6). Is it possible that α-secretase is stimulated by local Ca2+ influx via CALHM1 but not by a global Ca2+ elevation? What mechanisms are responsible for the increase in amyloid production in conditions of global Ca2+ elevation? There is no doubt future studies will uncover additional connections between Ca2+ signaling and amyloid processing. It may well be that the “Ca2+ hypothesis of AD” and the “amyloid hypothesis of AD” are much more closely related to each other than it initially appears.

    View all comments by Ilya Bezprozvanny
  5. Converging evidence strongly supports the notion that intracellular calcium is a key player in the regulation of APP metabolism. The different studies that have investigated this mechanism have, however, generated puzzling results, making it difficult to reconcile approaches targeting different pathways involved in calcium homeostasis. Our recent work shows that increased cytosolic calcium concentrations, by overexpression of CALHM1, massively promotes sAPPα secretion and represses Aβ extracellular accumulation. In line with this observation, it has been shown that manipulations increasing cytosolic calcium levels, by the use of sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) inhibitors or by RNA interference of SERCA2b, lead to a similar effect on APP processing: 1) by reducing Aβ accumulation (Green et al., 2008; Buxbaum et al., 1994), and 2) by promoting sAPPα secretion (Buxbaum et al., 1994). Furthermore, there is evidence that activation of capacitive calcium entry (CCE), a mechanism activated by SERCA inhibition, results in a robust stimulation of sAPPα (Kim et al., 2006) and in a decrease of Aβ42 levels (Yoo et al., 2000). This suggests that interventions leading to an increase of cytosolic calcium concentration (by CALHM1-mediated calcium entry, CCE, or SERCA inhibition) efficiently affect APP processing to prevent extracellular Aβ accumulation. It has been suggested, however, that APP processing might be more susceptible to ER calcium variations than actual cytosolic calcium concentrations (LaFerla, 2002). Given that CALHM1 is localized at both the plasma membrane and the ER surface, it may also affect APP metabolism by influencing ER calcium stores thereby. Testing of this hypothesis may help to reconcile today's apparently conflicting results.

    An important question is, How do we reconcile this proposed mechanism with the effect of AD-linked mutations in proteins implicated in calcium homeostasis? We proposed that the P86L polymorphism in CALHM1, which is associated with an increased risk of developing the disease, confers a partial loss of CALHM1 function. This partial loss of function results in reduced cell surface calcium permeability, lower levels of cytosolic calcium, and increased Aβ levels. Consistent with these results, LaFerla and colleagues reported enhanced SERCA-mediated clearance of cytosolic calcium by the FAD-linked M146V PS1 mutant, as compared to wild-type PS1 (Green et al., 2008). Together, this suggests that reduced cytosolic calcium content, and maybe also ER calcium overload, is/are key in Aβ elevations and may be directly relevant to the neurodegenerative process of AD.

    View all comments by Philippe Marambaud

References

News Citations

  1. Presenilins Open Escape Hatch for ER Calcium

Paper Citations

  1. . The pathogenesis of Alzheimers disease is it a lifelong "calciumopathy"?. Neuroscientist. 2007 Oct;13(5):546-59. PubMed.
  2. . TissueInfo: high-throughput identification of tissue expression profiles and specificity. Nucleic Acids Res. 2001 Nov 1;29(21):E102-2. PubMed.
  3. . Calcium hypothesis of Alzheimer's disease and brain aging. Ann N Y Acad Sci. 1994 Dec 15;747:1-11. PubMed.
  4. . 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.
  5. . A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell. 2008 Jun 27;133(7):1149-61. PubMed.

External Citations

  1. Alzgene database
  2. Lou Ruvo Brain Institute

Further Reading

Papers

  1. . The pathogenesis of Alzheimers disease is it a lifelong "calciumopathy"?. Neuroscientist. 2007 Oct;13(5):546-59. PubMed.
  2. . Calcium hypothesis of Alzheimer's disease and brain aging. Ann N Y Acad Sci. 1994 Dec 15;747:1-11. PubMed.
  3. . 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.
  4. . A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell. 2008 Jun 27;133(7):1149-61. PubMed.

Primary Papers

  1. . 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.
  2. . A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell. 2008 Jun 27;133(7):1149-61. PubMed.