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Alzheimer’s Disease: A short introduction to the calmodulin hypothesis

1 Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5
2 Department of Biology, University of Toronto Mississauga, Mississauga, Ontario, Canada L5L 1C6

Special Issues: Alzheimer’s Disease

At the cellular level, Alzheimer’s disease (AD) is characterized by the presence of intracellular plaques containing amyloid beta (Aβ) protein and neurofibrillary tangles consisting of phospho-tau (p-tau). These biomarkers are considered to contribute, at least in part, to the neurodegenerative events of the disease. But the accumulation of plaques and tangles is widely considered to be a later event with other factors likely being the cause of the disease. Calcium dysregulation—the unregulated accumulation of calcium ions—in neurons is an early event that underlies neurodegeneration. In 2002, O’Day and Myre extended this “Calcium Hypothesis” to include calmodulin (CaM) the primary target of calcium, suggesting the “Calmodulin Hypothesis” as an updated alternative. Here we overview the central role of CaM in the formation of the classic hallmarks of AD: plaques and tangles. Then some insight into CaM’s binding to various risk factor proteins is given followed by a short summary of specific receptors and channels linked to the disease that are CaM binding proteins. Overall, this review emphasizes the diversity of Alzheimer’s-linked CaM-binding proteins validating the hypothesis that CaM operates critically at all stages of the disease and stands out as a potential primary target for future research.
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References

1. Alzheimer's Association Calcium Hypothesis Workgroup (2017) Calcium hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement 13: 178–182.    

2. Khachaturian ZS (1994) Calcium hypothesis of Alzheimer's disease and brain aging. Ann N Y Acad Sci 747: 1–11.

3. Marx J (2007) Fresh evidence points to an old suspect: Calcium. Science 318: 384–385.    

4. O'Day DH, Myre MA (2004) Calmodulin-binding domains in Alzheimer's disease proteins: extending the calcium hypothesis. Biochem Biophys Res Commun 230: 1051–1054.

5. Brini M, Cali T, Ottolini D, et al. (2014) Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci 71: 2787–2814.    

6. Berridge MJ (2010) Calcium hypothesis of Alzheimer's disease. Pflüg Arch Eur J Phy 459: 441–449.    

7. Pepke S, Kinzer-Ursem T, Mihala S, et al. (2010) A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II. PLoS Comput Biol 6: e1000675.    

8. Chin D, Means AR (2000) Calmodulin: A prototypical calcium sensor. Trends Cell Biol 10: 322–328.    

9. Rhoads AR, Friedberg F (1997) Sequence motifs for calmodulin recognition. FASEB J 11: 331–340.    

10. Tidow H, Nissen P (2013) Structural diversity of calmodulin binding to its target sites. FEBS J 280: 5551–5565.    

11. Sharma RK, Parameswaran S (2018) Calmodulin-binding proteins: A journey of 40 years. Cell Calcium 75: 89–100.    

12. Hippius H, Neundörfer G (2003) The discovery of Alzheimer's disease. Dialogues Clin Neurosci 5: 101–108.

13. Myre MA, Tesco G, Tanzi RE, et al. (2005) Calmodulin binding to APP and the APLPs. Molecular Mechanisms of Neurodegeneration: A Joint Biochemical Society/Neuroscience Ireland Focused Meeting; March 13–16, University College Dublin, Republic of Ireland.

14. Canobbio I, Catricalà S, Balduini C, et al. (2011) Calmodulin regulates the non-amyloidogenic metabolism of amyloid precursor protein in platelets. Biochem Biophys Acta 1813: 500–506.    

15. Chavez SE, O'Day DH (2007) Calmodulin binds to and regulates the activity of beta-secretase (BACE1). Curr Res Alzheimers Dis 1: 37–47.

16. Corbacho I, Berrocal M, Torok K, et al. (2017) High affinity binding of amyloid β-peptide to calmodulin: Structural and functional implications. Biochem Biophys Res Commun 486: 992–997.    

17. Cline EN, Bicca MA, Viola KL, et al. (2018) The amyloid-β oligomer hypothesis: Beginning of the third decade. J Alzheimers Dis 64: S567–S610.    

18. O'Day DH, Eshak K, Myre MA (2015) Calmodulin binding proteins and Alzheimer's disease: A review. J Alzheimers Dis 46: 553–569.    

19. Michno K, Knight D, Campusano JM, et al. (2009) Intracellular calcium deficits in Drosophila cholinergic neurons expressing wild type or FAD-mutant presenilin. PLoS One 4: e6904.    

20. Lee YC, Wolff J (1984) Calmodulin binds to both microtubule-associated protein 2 and tau proteins. J Biol Chem 259: 1226–1230.

21. Padilla R, Maccioni RB, Avila J (1990) Calmodulin binds to a tubulin binding site of the microtubule-associated protein tau. Mol Cell Biochem 97: 35–41.

22. Huber RJ, Catalano A, O'Day DH (2013) Cyclin-dependent kinase 5 is a calmodulin-binding protein that associates with puromycin-sensitive aminopeptidase in the nucleus of Dictyostelium. Biochem Biophys Acta 1833: 11–20.    

23. Yu DY, Tong L, Song GJ, et al. (2008) Tau binds both subunits of calcineurin, and binding is impaired by calmodulin. Biochem Biophys Acta 1783: 2255–2261.    

24. Ghosh A, Geise KP (2015) Calcium/calmodulin-dependent kinase II and Alzheimer's disease. Mol Brain 8: 78.    

25. Reese LC, Taglialatela G (2011) A role for calcineurin in Alzheimer's disease. Curr Neuropharmacol 9: 685–692.    

26. Karch CM, Goate AM (2015) Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psych 77: 43–51.    

27. Newcombe EA Camats-Perna J, Silva ML, et al. (2018) Inflammation: The link between comorbidities, genetics and Alzheimer's disease. J Neuroinflamm 15: 276.    

28. Di Batista AM, Heinsinger NM, Rebeck GW (2016) Alzheimer's disease genetic risk factor APOE-4 also affects normal brain function. Curr Alzheimer Res 13: 1200–1207.    

29. Hansen DV, Hanson JE, Sheng M (2017) Microglia in Alzheimer's disease. J Cell Biol 217: 459–172.

30. Navarro V, Sanchez-Mejias E, Jimenez S, et al. (2018) Microglia in Alzheimer's disease: Activated, dysfunctional or degenerative. Front Aging Neurosci 10: 140.    

31. Jiang S, Li Y, Zhang C, et al. (2014) M1 muscarinic acetylcholine receptor in Alzheimer's disease. Neurosci Bull 30: 295–307.    

32. Lucas JL, Wang D, Sadée W (2006) Calmodulin binding to peptides derived from the i3 loop of muscarinic receptors. Pharm Res 23: 647–653.    

33. Berrocal M, Sepulveda MR, Vazquez-Hernandez M, et al. (2012) Calmodulin antagonizes amyloid-β peptides-mediated inhibition of brain plasma membrane Ca2+-ATPase. Biochim Biophys Acta 1822: 961–969.    

34. Ehlers MD, Zhang S, Bernhadt JP, et al. (1996) Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84: 745–755.    

35. Rycroft BK, Gibb AJ (2002) Direct effects of calmodulin on NMDA receptor single-channel gating in rat hippocampal granule cells. J Neurosci 22: 8860–8868.    

36. Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimers Dis 57: 1041–1048.    

37. Hong HS, Hwang JY, Son SM, et al. (2010) FK506 reduces amyloid plaque burden and induces MMP-9 in AβPP/PS1 double transgenic mice. J Alzheimers Dis 22: 97–105.    

38. Rozkalne A, Hyman BT, Spires-Jones TL (2011) Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice. Neurobiol Dis 41: 650–654.    

39. Taglialatella G, Rastellini C, Cicalese L (2015) Reduced incidence of dementia in solid organ transplant patients treated with calcineurin inhibitors. J Alzheimers Dis 47: 329–333.    

40. Popugaeva E, Pchitskaya E, Bezprozvanny I (2017) Dysregulation of neuronal calcium homeostasis in Alzheimer's disease-A therapeutic opportunity? Biochem Biophys Res Commun 483: 998–1004.    

© 2019 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

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