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...  Read more

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

2. Smith IF, Green KN, Laferla FM. Calcium dysregulation in Alzheimer's disease: recent advances gained from genetically modified animals. Cell Calcium. 2005 Sep-Oct;38(3-4):427-37. Abstract

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

4. Cai C, Lin P, Cheung KH, Li N, Levchook C, Pan Z, Ferrante C, Boulianne GL, Foskett JK, Danielpour D, Ma J. The presenilin-2 loop peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis. J Biol Chem. 2006 Jun 16;281(24):16649-55. Abstract

5. Rybalchenko V, Hwang SY, Rybalchenko N, Koulen P. The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity. Int J Biochem Cell Biol. 2008;40(1):84-97. Abstract

6. Pack-Chung E, Meyers MB, Pettingell WP, Moir RD, Brownawell AM, Cheng I, Tanzi RE, Kim TW. Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor. J Biol Chem. 2000 May 12;275(19):14440-5. Abstract

7. Tang TS, Tu H, Chan EY, Maximov A, Wang Z, Wellington CL, Hayden MR, Bezprozvanny I. 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. Abstract

8. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell. 2006 Sep 8;126(5):981-93. Abstract

9. Nelson O, Tu H, Lei T, Bentahir M, De Strooper B, Bezprozvanny I. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Abstract

10. Stutzmann GE, Caccamo A, Laferla FM, Parker I. 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. Abstract

11. Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I. 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. Abstract

12. Yoo AS, Cheng I, Chung S, Grenfell TZ, Lee H, Pack-Chung E, Handler M, Shen J, Xia W, Tesco G, Saunders AJ, Ding K, Frosch MP, Tanzi RE, Kim TW. Presenilin-mediated modulation of capacitative calcium entry. Neuron. 2000 Sep;27(3):561-72. Abstract

13. Ris L, Dewachter I, Reversé D, Godaux E, Van Leuven F. Capacitative calcium entry induces hippocampal long term potentiation in the absence of presenilin-1. J Biol Chem. 2003 Nov 7;278(45):44393-9. Abstract

14. Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, Van Leuven F. 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. Abstract

15. Takeda T, Asahi M, Yamaguchi O, Hikoso S, Nakayama H, Kusakari Y, Kawai M, Hongo K, Higuchi Y, Kashiwase K, Watanabe T, Taniike M, Nakai A, Nishida K, Kurihara S, Donoviel DB, Bernstein A, Tomita T, Iwatsubo T, Hori M, Otsu K. Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling. FASEB J. 2005 Dec;19(14):2069-71. Abstract

View all comments by Ilya Bezprozvanny

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...  Read more

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 (Beth) Stutzmann

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...  Read more

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.

References:
1. Smith IF, Green KN, Laferla FM. Calcium dysregulation in Alzheimer's disease: recent advances gained from genetically modified animals. Cell Calcium. 2005 Sep-Oct;38(3-4):427-37. Abstract

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

3. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell. 2006 Sep 8;126(5):981-93. Abstract

4. Nelson O, Tu H, Lei T, Bentahir M, De Strooper B, Bezprozvanny I. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Abstract

5. Querfurth HW, Selkoe DJ. Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry. 1994 Apr 19;33(15):4550-61. Abstract

6. Pierrot N, Ghisdal P, Caumont AS, Octave JN. Intraneuronal amyloid-beta1-42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death. J Neurochem. 2004 Mar;88(5):1140-50. Abstract

View all comments by Ilya Bezprozvanny

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...  Read more

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:
Foskett JK, White C, Cheung KH, Mak DO. Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev. 2007 Apr;87(2):593-658. Abstract

Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I. 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. Abstract

Smith IF, Hitt B, Green KN, Oddo S, Laferla FM. Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer's disease. J Neurochem. 2005 Sep;94(6):1711-8. Abstract

Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell. 2006 Sep 8;126(5):981-93. Abstract

View all comments by Grace (Beth) Stutzmann

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)...  Read more

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.

References:
Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, Laferla FM. SERCA pump activity is physiologically regulated by presenilin and regulates amyloid {beta} production. J Cell Biol. 2008 Jun 30;181(7):1107-16. Abstract

Buxbaum JD, Ruefli AA, Parker CA, Cypess AM, Greengard P. Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4489-93. Abstract

Kim JH, Choi S, Jung JE, Roh EJ, Kim HJ. Capacitative Ca2+ entry is involved in regulating soluble amyloid precursor protein (sAPPalpha) release mediated by muscarinic acetylcholine receptor activation in neuroblastoma SH-SY5Y cells. J Neurochem. 2006 Apr;97(1):245-54. Abstract

Yoo AS, Cheng I, Chung S, Grenfell TZ, Lee H, Pack-Chung E, Handler M, Shen J, Xia W, Tesco G, Saunders AJ, Ding K, Frosch MP, Tanzi RE, Kim TW. Presenilin-mediated modulation of capacitative calcium entry. Neuron. 2000 Sep;27(3):561-72. Abstract

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

View all comments by Philippe Marambaud