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


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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.

  2. 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.


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  3. 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.


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This paper appears in the following:


  1. Channel Surfing—Two Studies Strengthen Calcium-AD Connection