Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Free Access

Can the Calcium Hypothesis Explain Synaptic Loss in Alzheimer's Disease?

Popugaeva E.a · Bezprozvanny I.a, b

Author affiliations

aLaboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg, Russia; bDepartment of Physiology, UT Southwestern Medical Center at Dallas, Dallas, Tex., USA

Corresponding Author

Ilya Bezprozvanny

Department of Physiology, ND12.200AA, UT Southwestern Medical Center at Dallas

5323 Harry Hines Blvd.

Dallas, TX 75390-9040 (USA)

E-Mail Ilya.Bezprozvanny@UTSouthwestern.edu

Related Articles for ""

Neurodegener Dis 2014;13:139-141

Abstract

Alzheimer's disease (AD) is the threat of modern humankind that is provoked by increased human lifespan. Despite extensive studies on AD pathology for more than 100 years, there are no disease-preventing therapies. Growing evidence suggests the role of calcium (Ca2+) in the pathogenesis of AD. The main purpose of the article is to understand whether modern science is able to explain the synapse loss observed in early AD and discuss the role of Ca2+ hypothesis in it. Based on results obtained in our laboratory and others, we propose that familial AD-associated mutations in presenilins cause a Ca2+ overload of endoplasmic reticulum stores which leads to compensatory downregulation of the neuronal store-operated Ca2+ (nSOC) entry pathway. We propose that synaptic nSOC is necessary for the stability of mature synaptic spines and that dysfunction of this pathway may play an important role in synaptic and memory loss in AD.

© 2013 S. Karger AG, Basel


Alzheimer's disease (AD) is a well-known pathology destroying the human brain and the personality. The majority of known facts about AD pathogenesis come from discoveries in mouse models mimicking genetically caused cases of familial AD (FAD). Although FAD covers about 1-2% of all AD cases, the mouse models and clinical data agree that synapse loss is the major hallmark of AD that results in memory loss.

What is the physiological substrate of memory? Expression of long-term potentiation in response to brief high-frequency stimulation of synaptic ends in the hippocampus is strongly correlated with learning and memory [1,2]. Long-term potentiation takes place in small dendritic protrusions called dendritic spines. Based on their size and shape, spines are divided into three groups: stubby, thin and mushroom. It has been proposed that the mushroom spines are stable ‘memory spines', and therefore, they store memories, and that thin spines are ‘learning spines' that serve as physical substrates for the formation of new memories [3,4]. Since loss of memories is a hallmark of AD, we and others previously proposed that mushroom spines are more likely to be eliminated during AD progression [5,6,7].

What mechanism is responsible for mushroom spine elimination? The dominant amyloid-β (Aβ)-based hypothesis of AD states that soluble Aβ42 peptides possess synaptotoxic effects. Aβ could mediate the synapse loss through the potentiation of the N-methyl-D-aspartate receptor. Stimulation of the N-methyl-D-aspartate receptor triggers excessive calcium (Ca2+) influx that activates calcineurin, a Ca2+-activated phosphatase whose activation leads to synapse weakening and AD-associated spine loss [8]. However, many facts speak for early Ca2+ abnormalities that precede or even happen in the absence of Aβ pathology [9,10]. The Ca2+ hypothesis of brain aging and AD states for sustained changes in Ca2+ homeostasis could provide the common pathway for aging and the neuropathological changes associated with AD [11]. In particular, multiple evidence points to disregulated endoplasmic reticulum (ER) Ca2+ homeostasis in aging and AD neurons [9,10]. There are two channels in the ER that mediate Ca2+ release: ryanodine receptors (RyanR) and inositol triphosphate receptors (IP3R). Taking into account that IP3R predominantly resides in the soma, whereas RyanR-mediated signals are more distinct in dendritic spines and presynaptic terminals [12,13], the input of abnormal RyanR function on postsynaptic Ca2+ signaling could be stronger than IP3R-mediated signaling. Thus, blocking RyanR (for example with dantrolene) appears to be a potential way to stabilize Ca2+ signals in AD brains. However, inconsistent results were obtained when dantrolene was tested in AD mouse models [14,15,16,17].

In addition to RyanR and IP3R, our recent data show that presenilins (PS; mutations in PS are associated with FAD) could play the role of a low conductance ER Ca2+ leak channel, and many FAD mutations disrupt this function [18]. This idea remains controversial [19], but our hypothesis has found confirmation in a recent breakthrough study that demonstrates the crystal structure of a bacterial homologue of PS (PSH) [20]. In agreement with our mutagenesis data [21], the authors found that PSH has a water-filled hole that is large enough to allow the passage of small ions, suggesting that PSH may function as an ion channel. Our hypothesis was also supported by a recent unbiased screen for Ca2+ homeostasis modulators [22]. These authors demonstrated that knocking down PS2 dramatically reduced the ER Ca2+ leak rate in HEK293 cells, consistent with the ‘leak channel' hypothesis [22,23].

What is the connection between impaired ER Ca2+ leak function, ER Ca2+ overload and synaptic loss in AD? We previously proposed that abnormalities in ER Ca2+ handling may be linked to destabilization of mushroom postsynaptic spines [6,7]. Consistent with this idea, in recent experiments, we observed a significant downregulation of the synaptic neuronal store-operated Ca2+ (nSOC) entry pathway in PS mutant neurons [Sun and Bezprozvanny, unpubl. data]. In agreement with our findings, impaired SOC was reported by several groups for PS mutant cells [16,24,25,26,27,28]. Our results further indicate that reduced postsynaptic SOC leads to destabilization and elimination of mushroom spines - sites of memory storage [Sun and Bezprozvanny, unpubl. data].

Based on obtained results, we propose that synaptic ER Ca2+ overload and compensatory downregulation of the synaptic nSOC pathway play an important role in synaptic loss in AD and aging brains. Our results suggest that upregulation of the synaptic nSOC pathway may yield therapeutic benefits for the treatment of AD and age-related memory problems.

Acknowledgments

I.B. is a holder of the Carl J. and Hortense M. Thomsen Chair in Alzheimer's Disease Research. This work was supported by Welch Foundation I-1754 (I.B.), National Institutes of Health grant R01NS080152 (I.B.), by the contract with the Russian Ministry of Science 11.G34.31.0056 (I.B.), and by the Dynasty Foundation grant DP-B-11/13 (E.P.).


References

  1. Bliss TV, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993;361:31-39.
  2. Trommald M, Hulleberg G, Andersen P: Long-term potentiation is associated with new excitatory spine synapses on rat dentate granule cells. Learn Mem 1996;3:218-228.
    External Resources
  3. Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H: Structure-stability-function relationships of dendritic spines. Trends Neurosci 2003;26:360-368.
  4. Bourne J, Harris KM: Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol 2007;17:381-386.
  5. Tackenberg C, Ghori A, Brandt R: Thin, stubby or mushroom: spine pathology in Alzheimer's disease. Curr Alzheimer Res 2009;6:261-268.
  6. Popugaeva E, Supnet C, Bezprozvanny I: Presenilins, deranged calcium homeostasis, synaptic loss and dysfunction in Alzheimer's disease. Messenger 2012;1:53-62.
    External Resources
  7. Bezprozvanny I, Hiesinger PR: The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol Neurodegener 2013;8:23.
  8. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT: Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 2010;30:2636-2649.
  9. Bezprozvanny I, Mattson MP: Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 2008;31:454-463.
  10. Stutzmann GE: The pathogenesis of Alzheimers disease is it a lifelong ‘calciumopathy'? Neuroscientist 2007;13:546-559.
  11. Khachaturian ZS: Calcium, membranes, aging, and Alzheimer's disease. Introduction and overview. Ann NY Acad Sci 1989;568:1-4.
  12. 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;94:1711-1718.
  13. Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE, Foskett JK: Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal 2010;3:ra22.
  14. Oules B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Brechot P, Trebak M, Checler F, Benfenati F, Chami M: Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 2012;32:11820-11834.
  15. Chakroborty S, Briggs C, Miller MB, Goussakov I, Schneider C, Kim J, Wicks J, Richardson JC, Conklin V, Cameransi BG, Stutzmann GE: Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer's disease. PLoS One 2012;7:e52056.
  16. Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I: Role of presenilins in neuronal calcium homeostasis. J Neurosci 2010;30:8566-8580.
  17. Peng J, Liang G, Inan S, Wu Z, Joseph DJ, Meng Q, Peng Y, Eckenhoff MF, Wei H: Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett 2012;516:274-279.
  18. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee S-F, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I: Presenilins form ER calcium leak channels, a function disrupted by mutations linked to familial Alzheimer's disease. Cell 2006;126:981-993.
  19. Shilling D, Mak DO, Kang DE, Foskett JK: Lack of evidence for presenilins as endoplasmic reticulum Ca2+ leak channels. J Biol Chem 2012;287:10933-10944.
  20. Li X, Dang S, Yan C, Gong X, Wang J, Shi Y: Structure of a presenilin family intramembrane aspartate protease. Nature 2013;493:56-61.
  21. Nelson O, Supnet C, Tolia A, Horre K, De Strooper B, Bezprozvanny I: Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. J Biol Chem 2011;286:22339-22347.
  22. Bandara S, Malmersjö S, Meyer T: Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA. Sci Signal 2013;6:ra56.
  23. Bezprozvanny I: Presenilins and calcium signaling - systems biology to the rescue. Sci Signal 2013;6:pe24.
  24. Leissring MA, Akbari Y, Fanger CM, Cahalan MD, Mattson MP, LaFerla FM: Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 2000;149:793-798.
  25. 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;27:561-572.
  26. 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;278:2484-2489.
  27. Akbari Y, Hitt BD, Murphy MP, Dagher NN, Tseng BP, Green KN, Golde TE, LaFerla FM: Presenilin regulates capacitative calcium entry dependently and independently of gamma-secretase activity. Biochem Biophys Res Commun 2004;322:1145-1152.
  28. Bojarski L, Pomorski P, Szybinska A, Drab M, Skibinska-Kijek A, Gruszczynska-Biegala J, Kuznicki J: Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca2+ entry in familial Alzheimer's disease. Biochim Biophys Acta 2009;1793:1050-1057.

Author Contacts

Ilya Bezprozvanny

Department of Physiology, ND12.200AA, UT Southwestern Medical Center at Dallas

5323 Harry Hines Blvd.

Dallas, TX 75390-9040 (USA)

E-Mail Ilya.Bezprozvanny@UTSouthwestern.edu


Article / Publication Details

First-Page Preview
Abstract of  

Received: May 07, 2013
Accepted: August 01, 2013
Published online: September 24, 2013
Issue release date: January 2014

Number of Print Pages: 3
Number of Figures: 0
Number of Tables: 0

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Bliss TV, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993;361:31-39.
  2. Trommald M, Hulleberg G, Andersen P: Long-term potentiation is associated with new excitatory spine synapses on rat dentate granule cells. Learn Mem 1996;3:218-228.
    External Resources
  3. Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H: Structure-stability-function relationships of dendritic spines. Trends Neurosci 2003;26:360-368.
  4. Bourne J, Harris KM: Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol 2007;17:381-386.
  5. Tackenberg C, Ghori A, Brandt R: Thin, stubby or mushroom: spine pathology in Alzheimer's disease. Curr Alzheimer Res 2009;6:261-268.
  6. Popugaeva E, Supnet C, Bezprozvanny I: Presenilins, deranged calcium homeostasis, synaptic loss and dysfunction in Alzheimer's disease. Messenger 2012;1:53-62.
    External Resources
  7. Bezprozvanny I, Hiesinger PR: The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol Neurodegener 2013;8:23.
  8. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT: Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 2010;30:2636-2649.
  9. Bezprozvanny I, Mattson MP: Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 2008;31:454-463.
  10. Stutzmann GE: The pathogenesis of Alzheimers disease is it a lifelong ‘calciumopathy'? Neuroscientist 2007;13:546-559.
  11. Khachaturian ZS: Calcium, membranes, aging, and Alzheimer's disease. Introduction and overview. Ann NY Acad Sci 1989;568:1-4.
  12. 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;94:1711-1718.
  13. Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE, Foskett JK: Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal 2010;3:ra22.
  14. Oules B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Brechot P, Trebak M, Checler F, Benfenati F, Chami M: Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 2012;32:11820-11834.
  15. Chakroborty S, Briggs C, Miller MB, Goussakov I, Schneider C, Kim J, Wicks J, Richardson JC, Conklin V, Cameransi BG, Stutzmann GE: Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer's disease. PLoS One 2012;7:e52056.
  16. Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I: Role of presenilins in neuronal calcium homeostasis. J Neurosci 2010;30:8566-8580.
  17. Peng J, Liang G, Inan S, Wu Z, Joseph DJ, Meng Q, Peng Y, Eckenhoff MF, Wei H: Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett 2012;516:274-279.
  18. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee S-F, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I: Presenilins form ER calcium leak channels, a function disrupted by mutations linked to familial Alzheimer's disease. Cell 2006;126:981-993.
  19. Shilling D, Mak DO, Kang DE, Foskett JK: Lack of evidence for presenilins as endoplasmic reticulum Ca2+ leak channels. J Biol Chem 2012;287:10933-10944.
  20. Li X, Dang S, Yan C, Gong X, Wang J, Shi Y: Structure of a presenilin family intramembrane aspartate protease. Nature 2013;493:56-61.
  21. Nelson O, Supnet C, Tolia A, Horre K, De Strooper B, Bezprozvanny I: Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. J Biol Chem 2011;286:22339-22347.
  22. Bandara S, Malmersjö S, Meyer T: Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA. Sci Signal 2013;6:ra56.
  23. Bezprozvanny I: Presenilins and calcium signaling - systems biology to the rescue. Sci Signal 2013;6:pe24.
  24. Leissring MA, Akbari Y, Fanger CM, Cahalan MD, Mattson MP, LaFerla FM: Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 2000;149:793-798.
  25. 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;27:561-572.
  26. 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;278:2484-2489.
  27. Akbari Y, Hitt BD, Murphy MP, Dagher NN, Tseng BP, Green KN, Golde TE, LaFerla FM: Presenilin regulates capacitative calcium entry dependently and independently of gamma-secretase activity. Biochem Biophys Res Commun 2004;322:1145-1152.
  28. Bojarski L, Pomorski P, Szybinska A, Drab M, Skibinska-Kijek A, Gruszczynska-Biegala J, Kuznicki J: Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca2+ entry in familial Alzheimer's disease. Biochim Biophys Acta 2009;1793:1050-1057.
Figures

Tables