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Calcium hypothesis of Alzheimer’s disease

  • Signaling and Cell Physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca2+ signaling pathways responsible for cognition. Hydrolysis of the β-amyloid precursor protein (APP) yields two products that can influence Ca2+ signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca2+ that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca2+ within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca2+ being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca2+ signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca2+ signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca2+-dependent protein phosphatase calcineurin. The alteration in Ca2+ signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.

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References

  1. Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 31:454–463

    Article  CAS  PubMed  Google Scholar 

  2. Bojarski L, Herms J, Kuznicki J (2008) Calcium dysregulation in Alzheimer's disease. Neurochem Int 52:621–633

    Article  CAS  PubMed  Google Scholar 

  3. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science 321:1686–1689

    Article  CAS  PubMed  Google Scholar 

  4. Cao X, Südhof TC (2001) A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293:115–120

    Article  CAS  PubMed  Google Scholar 

  5. Chakroborty S, Goussakov I, Miller MB, Stutzmann GE (2009) Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3 × Tg-AD mice. J Neurosci 29:9458–9470

    Article  CAS  PubMed  Google Scholar 

  6. Chan SL, Mayne M, Holden CP, Geiger JD, Mattson MP (2000) Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem 275:18195–18200

    Article  CAS  PubMed  Google Scholar 

  7. Cheung K-H, Shineman D, Müller M, Cárdenas C, Mei L, Yang J, Tomita T, Iwatsubo T, M-Y LV, Foskett JK (2008) Mechanisms of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58:871–883

    Article  CAS  PubMed  Google Scholar 

  8. Citri A, Malenka RM (2008) Synaptic plasticity: multiple forms, and mechanisms. Neuropsychopharmacology Rev 33:18–41

    Article  Google Scholar 

  9. Dineley KT, Hogan D, Zhang WR, Taglialatela G (2007) Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem 88:217–224

    Article  CAS  PubMed  Google Scholar 

  10. Dreses-Werringloer U, Lambert J-C, Vingtdeux V, Zhao H, Vais H, Siebert A et al (2008) A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβ levels, and Alzheimer's disease risk. Cell 133:1149–1161

    Article  CAS  PubMed  Google Scholar 

  11. Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A (2001) Calcineurin links Ca2+ dysregulation with brain aging. J Neurosci 21:4066–4073

    CAS  PubMed  Google Scholar 

  12. Geula C, Bu J, Nagykery N, Scinto LFM, Chan J, Joseph J, Parker R, Wu C-K (2003) Loss of calbindin-D28K from aging human cholinergic basal forebrain: relation to neuronal loss. J Comp Neurol 455:249–259

    Article  CAS  PubMed  Google Scholar 

  13. Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LeFerla FM (2008) SERCA pump activity is physiologically regulated by presenilin and regulates amyloid β production. J Cell Biol 181:1107–1116

    Article  CAS  PubMed  Google Scholar 

  14. Green KN, LaFerla FM (2008) Linking calcium to Aβ and Alzheimer's disease. Neuron 59:190194

    Article  Google Scholar 

  15. Guo Q, Furukawa K, Sopher BL, Pham DG, Xie J, Robinson N, Martin GM, Mattson MP (1996) Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid betapeptide. NeuroReport 8:379–383

    Article  CAS  PubMed  Google Scholar 

  16. Guo Q, Christakos S, Robinson N, Mattson MP (1998) Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function. Proc Natl Acad Sci 95:3227–3232

    Article  CAS  PubMed  Google Scholar 

  17. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  PubMed  Google Scholar 

  18. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  19. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843

    Article  CAS  PubMed  Google Scholar 

  20. Ichimiya Y, Emson PC, Mountjoy CQ, Lawson DE, Heizmann CW (1988) Loss of calbindin-28 K immunoreactive neurones from the cortex in Alzheimer-type dementia. Brain Res 475:156–159

    Article  CAS  PubMed  Google Scholar 

  21. Jacobsen JS, Wu C-C, Redwine JM, Comery TA, Arias R, Bowlby M et al (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci 103:5161–5166

    Article  CAS  PubMed  Google Scholar 

  22. Jiang Q, Lee CYD, Mandrekar S, Wilkinson B et al (2008) ApoE promotes the proteolytic degradation of A β. Neuron 58:681–693

    Article  CAS  PubMed  Google Scholar 

  23. Kasri NN, Kocks SL, Verbert L, Hébert SS, Callewaert G, Parys JB, Missiaen L, De Smedt H (2006) Up-regulation of inositol 1, 4, 5-trisphosphate receptor type 1 is responsible for a decreased endoplasmic-reticulum Ca2+ content of presenilin double knock-out cells. Cell Calcium 40:41–51

    Article  CAS  PubMed  Google Scholar 

  24. Khachaturian ZS (1989) Calcium, membranes, aging, and Alzheimer's disease. Introduction and overview. Ann N Y Acad Sci 568:1–4

    Article  CAS  PubMed  Google Scholar 

  25. Klyubin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, Betts V, Spooner ET, Jiang L, Anwyl R, Selkoe DJ, Rowan MJ (2005) Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat Med 11:556–561

    Article  CAS  PubMed  Google Scholar 

  26. Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu H-Y, Hyman BT, Bacskai BJ (2008) Aβ plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59:214–225

    Article  CAS  PubMed  Google Scholar 

  27. LaFerla FM (2002) Calcium dyshomeostasis and intracellular signaling in Alzheimer's disease. Nat Rev Neurosci 3:862–872

    Article  CAS  PubMed  Google Scholar 

  28. Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairement of synaptic plasticity by amyloid-β oligomers. Nature 457:1128–1132

    Article  PubMed  Google Scholar 

  29. Leissring MA, Murphy MP, Mead TR, Akbari Y, Sugarman MC et al (2002) A physiological signalling role for the γ-secretase-derived intracellular fragment of APP. Proc Natl Acad Sci 99:4697–4702

    Article  CAS  PubMed  Google Scholar 

  30. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloidbeta protein assembly in the brain impairs memory. Nature 440:352–357

    Article  CAS  PubMed  Google Scholar 

  31. Lopez JR, Lyckman A, Oddo S, LaFerla FM, Querfurth HW, Shtifman A (2008) Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice. J Neurochem 105:262–271

    Article  CAS  PubMed  Google Scholar 

  32. Mattson MP (2004) Pathways towards and away from Alzheimer's disease. Nature 430:631–639

    Article  CAS  PubMed  Google Scholar 

  33. Nikolaev A, McLaughlin T, O’Leary DDM, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989

    Article  CAS  PubMed  Google Scholar 

  34. Nixon RA (2007) Autophagy, amyloidogenesis and Alzheimer's disease. J Cell Sci 120:4081–4091

    Article  CAS  PubMed  Google Scholar 

  35. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    Article  CAS  PubMed  Google Scholar 

  36. Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ (2006) The lipoprotein receptor LR11 regulates amyloid β production and amyloid precursor protein traffic in endosomal compartments. J Neurosci 26:1596–1603

    Article  CAS  PubMed  Google Scholar 

  37. Palop JJ, Jones B, Kekonius L, Chin J, Yu G-Q, Raber L, Masliah E, Mucke L (2003) Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci 100:9572–9577

    Article  CAS  PubMed  Google Scholar 

  38. Pierrot N, Ghisdal P, Caumont AS, Octave JN (2004) Intraneuronal amyloid-beta1–42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death. J Neurochem 88:1140–1150

    Article  CAS  PubMed  Google Scholar 

  39. Pierrot N, Santos SF, Feyt C, Morel M, Brion JP, Octave JN (2006) Calcium-mediated transient phosphorylation of tau and amyloid precursor protein followed by intraneuronal amyloid-beta accumulation. J Biol Chem 281:39907–39914

    Article  CAS  PubMed  Google Scholar 

  40. Querfurth HW, Selkoe DJ (1994) Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 33:4550–4561

    Article  CAS  PubMed  Google Scholar 

  41. Rogaeva E et al (2007) The neuronal sortilin-related receptor SoRL1 is genetically associated with Alzheimer disease. Nature Genet 39:168–177

    Article  CAS  PubMed  Google Scholar 

  42. Rohn TT, Vyas V, Hernandez-Estrada T, Nichol KE, Christie L-A, Head E (2008) Lack of pathology in a triple transgenic mouse model of Alzheimer's disease after overexpression of the anti-apoptotic protein Bcl-2. J Neurosci 28:3051–3059

    Article  CAS  PubMed  Google Scholar 

  43. Rong YP, Distelhorst CW (2008) Bcl-2 protein family: versatile regulators of calcium signaling in cell survival and apoptosis. Ann Rev Physiol 70:73–91

    Article  CAS  Google Scholar 

  44. Sanz-Blesco S, Valero RA, Rodriguez-Crespo I, Villalobos C, Núñez L (2008) Mitochondrial Ca2+ overload underlies Aβ oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PloS One 3:e2718

    Article  Google Scholar 

  45. Shirwany NA, Payette D, Xie J, Guo Q (2007) The amyloid beta ion channel hypothesis of Alzheimer's disease. Neuropsychiatric Dis Treatment 3:597–612

    CAS  Google Scholar 

  46. Smith IF, Hitt B, Green KN, Oddo S, LaFerla FM (2005) Enhanced caffeine-induced Ca2+ release in the 3 × Tg-AD mouse model of Alzheimer's disease. J Neurochem 94:1711–1718

    Article  CAS  PubMed  Google Scholar 

  47. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051–1058

    Article  CAS  PubMed  Google Scholar 

  48. Stutzmann GE, Smith I, Caccamo A, Oddo S, LaFerla FM, Parker I (2006) Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult and aged Alzhemier’s disease mice. J. Neurosci 26:5180–5189

    Article  CAS  PubMed  Google Scholar 

  49. Stutzmann GE (2007) The pathogenesis of Alzheimer's disease- is it a lifelong “calciumopathy”. Neuroscientist 13:546–559

    Article  CAS  PubMed  Google Scholar 

  50. Supnet C, Grant J, Kong H, Westaway D, Mayne M (2006) Abeta 1–42 increases ryanodine receptor-3 expression and function in TgCRND8 mice. J Biol Chem 281:38440–38447

    Article  CAS  PubMed  Google Scholar 

  51. Thibault O, Gant JC, Landfield PW (2007) Expansion of the calcium hypothesis of brain ageing and Alzheimer's disease: minding the store. Ageing Cell 6:307–317

    Article  CAS  Google Scholar 

  52. Townsend M, Shankar GM, Mehta T, Walsh DM, Selkoe DJ (2006) Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol. 572:477–492

    Article  CAS  PubMed  Google Scholar 

  53. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, de Strooper B, Yu G, Bezprozvanny I (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126:981–993

    Article  CAS  PubMed  Google Scholar 

  54. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539

    Article  CAS  PubMed  Google Scholar 

  55. Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH (2002) The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci 22:1858–1867

    CAS  PubMed  Google Scholar 

  56. Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Südhof TC, Shen J (2009) Presenilins are essential for regulating neurotransmitter release. Nature 460:632–636

    Article  CAS  PubMed  Google Scholar 

  57. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Gen. doi:10.1038/ng.440

    Google Scholar 

  58. Lambert J-C, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Gen. doi:10.1038/ng.439

    Google Scholar 

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Note added in proof

Two very recent reports have identified new AD susceptibility genes (CLU, CR1 and PICALM) [57, 58], which provide further support for the hypotheses outlined in this review. CLU encodes the protein clustrin, which function like ApoE (see Fig. 2) to bind soluble amyloids to regulate their toxicity [57, 58]. CR1 is the gene for the complement component (3b/4b) receptor 1, which functions in the complement system to clear soluble amyloids [58]. PICALM encodes a phosphatidylinositol-binding clathrin assembly protein, which is located in pre- and post-synaptic neuronal endings where it plays a role in clathrin-mediated endocytosis [57]. The genetic modifications to PICALM may function to divert APP to the late endosomes to promote the formation of soluble amyloids (see step 4 in Figure 2). In addition, mutated PICALM may contribute to the decline in synaptic plasticity seen in AD by increasing the rate of endocytosis. Such an action would thus mirror the effect of elevated Ca2+ by enhancing the process of long-term depression (LTD), which might be one of the major defects responsible for early memory loss in AD.

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    Michael J. Berridge

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Berridge, M.J. Calcium hypothesis of Alzheimer’s disease. Pflugers Arch - Eur J Physiol 459, 441–449 (2010). https://doi.org/10.1007/s00424-009-0736-1

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