Advertisement

Alzheimer Disease

  • Estela Area-Gomez
  • Eric A. Schon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 997)

Abstract

The most widely accepted hypothesis to explain the pathogenesis of Alzheimer disease (AD) is the amyloid cascade, in which the accumulation of extraneuritic plaques and intracellular tangles plays a key role in driving the course and progression of the disease. However, there are other biochemical and morphological features of AD, including altered calcium, phospholipid, and cholesterol metabolism and altered mitochondrial dynamics and function that often appear early in the course of the disease, prior to plaque and tangle accumulation. Interestingly, these other functions are associated with a subdomain of the endoplasmic reticulum (ER) called mitochondria-associated ER membranes (MAM). MAM, which is an intracellular lipid raft-like domain, is closely apposed to mitochondria, both physically and biochemically. These MAM-localized functions are, in fact, increased significantly in various cellular and animal models of AD and in cells from AD patients, which could help explain the biochemical and morphological alterations seen in the disease. Based on these and other observations, a strong argument can be made that increased ER-mitochondria connectivity and increased MAM function are fundamental to AD pathogenesis.

Keywords

ApoE Cholesterol Cholesteryl esters Endoplasmic reticulum Lipid rafts MAM Membranes Mitochondria Mitochondria-associated ER membranes Neurodegeneration Phospholipids 

Notes

Acknowledgments

This work was supported by the US Department of Defense (W911F-15-1-0169), the Ellison Medical Foundation, and the J. Willard and Alice S. Marriott Foundation (to EAS) and by the US National Institutes of Health (K01-AG045335 to E.A.-G.).

References

  1. Abe-Dohmae S, Ikeda Y, Matsuo M, Hayashi M, K-i O, Ueda K, Yokoyama S (2004) Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate high density lipoprotein. J Biol Chem 279:604–611CrossRefPubMedGoogle Scholar
  2. Area-Gomez E, Del Carmen Lara Castillo M, Tambini MD, Guardia-Laguarta C, de Groof AJC, Madra M, Ikenouchi J, Umeda M, Bird TD, Sturley SL et al (2012) Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J 31:4106–4123Google Scholar
  3. Area-Gomez E, Schon EA (2016) Mitochondria-associated ER membranes and Alzheimer disease. Curr Opin Genet Dev 38:90–96CrossRefPubMedPubMedCentralGoogle Scholar
  4. Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon LA et al (2009) Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol 175:1810–1816CrossRefPubMedPubMedCentralGoogle Scholar
  5. Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR (2012) The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336:1168–1171CrossRefPubMedPubMedCentralGoogle Scholar
  6. Beel AJ, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, Prestegard JH, Sanders CR (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry 47:9428–9446CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463CrossRefPubMedPubMedCentralGoogle Scholar
  8. Busciglio J, Hartmann H, Lorenzo A, Wong C, Baumann K, Sommer B, Staufenbiel M, Yankner BA (1997) Neuronal localization of presenilin-1 and association with amyloid plaques and neurofibrillary tangles in Alzheimer’s disease. J Neurosci 17:5101–5107PubMedGoogle Scholar
  9. Chan RB, Oliveira TG, Cortes EP, Honig LS, Duff KE, Small SA, Wenk MR, Shui G, Di Paolo G (2012) Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J Biol Chem 287:2678–2688CrossRefPubMedGoogle Scholar
  10. Csordas G, Renken C, Varnai P, Walter L, Weaver D, Buttle KF, Balla T, Mannella CA, Hajnoczky G (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174:915–921CrossRefPubMedPubMedCentralGoogle Scholar
  11. Csordas G, Varnai P, Golenar T, Roy S, Purkins G, Schneider TG, Balla T, Hajnoczky G (2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39:121–132CrossRefPubMedPubMedCentralGoogle Scholar
  12. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610CrossRefPubMedGoogle Scholar
  13. Di Paolo G, Kim TW (2011) Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nature reviews Neuroscience 12:284–296CrossRefPubMedPubMedCentralGoogle Scholar
  14. English AR, Voeltz GK (2013) Endoplasmic reticulum structure and interconnections with other organelles. Cold Spring Harb Perspect Biol 5:a013227CrossRefPubMedPubMedCentralGoogle Scholar
  15. Ferrer I (2009) Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer’s disease. J Bioenerg Biomembr 41:425–431CrossRefPubMedGoogle Scholar
  16. Fraser T, Tayler H, Love S (2010) Fatty acid composition of frontal, temporal and parietal neocortex in the normal human brain and in Alzheimer’s disease. Neurochem Res 35:503–513CrossRefPubMedGoogle Scholar
  17. Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK (2011) ER tubules mark sites of mitochondrial division. Science 334:358–362CrossRefPubMedPubMedCentralGoogle Scholar
  18. Gibson GE, Huang H-M (2004) Mitochondrial enzymes and endoplasmic reticulum calcium stores as targets of oxidative stress in neurodegenerative diseases. J Bioenerg Biomembr 36:335–340CrossRefPubMedGoogle Scholar
  19. Gibson GE, Vestling M, Zhang H, Szolosi S, Alkon D, Lannfelt L, Gandy S, Cowburn RF (1997) Abnormalities in Alzheimer’s disease fibroblasts bearing the APP670/671 mutation. Neurobiol Aging 18:573–580CrossRefPubMedGoogle Scholar
  20. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185CrossRefPubMedGoogle Scholar
  21. Hayashi T, Fujimoto M (2010) Detergent-resistant microdomains determine the localization of sigma-1 receptors to the endoplasmic reticulum-mitochondria junction. Mol Pharmacol 77:517–528CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hayashi T, Rizzuto R, Hajnoczky G, Su TP (2009) MAM: more than just a housekeeper. Trends Cell Biol 19:81–88CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hedskog L, Pinho CM, Filadi R, Ronnback A, Hertwig L, Wiehager B, Larssen P, Gellhaar S, Sandebring A, Westerlund M et al (2013) Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci USA 110:7916–7921CrossRefPubMedPubMedCentralGoogle Scholar
  24. Heeren J, Grewal T, Laatsch A, Rottke D, Rinninger F, Enrich C, Beisiegel U (2003) Recycling of apoprotein E is associated with cholesterol efflux and high density lipoprotein internalization. J Biol Chem 278:14370–14378CrossRefPubMedGoogle Scholar
  25. Heeren J, Grewal T, Laatsch A, Becker N, Rinninger F, Rye K-A, Beisiegel U (2004) Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation. J Biol Chem 279:55483–55492CrossRefPubMedGoogle Scholar
  26. Heilig EA, Xia W, Shen J, Kelleher RJ 3rd (2010) A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of γ-secretase activity. J Biol Chem 285:22350–22359CrossRefPubMedPubMedCentralGoogle Scholar
  27. Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2:a006312PubMedPubMedCentralGoogle Scholar
  28. Hoyer S, Oesterreich K, Wagner O (1988) Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J Neurol 235:143–148CrossRefPubMedGoogle Scholar
  29. Huang Y (2010) Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med 16:287–294CrossRefPubMedGoogle Scholar
  30. Jia W, Moulson CL, Pei Z, Miner JH, Watkins PA (2007) Fatty acid transport protein 4 is the principal very long chain fatty acyl-CoA synthetase in skin fibroblasts. J Biol Chem 282:20573–20583CrossRefPubMedGoogle Scholar
  31. Liang J, Kulasiri D, Samarasinghe S (2015) Ca2+ dysregulation in the endoplasmic reticulum related to Alzheimer’s disease: a review on experimental progress and computational modeling. Biosystems 134:1–15CrossRefPubMedGoogle Scholar
  32. Lingwood D, Simons K (2010) Lipid rafts as a membrane-organizing principle. Science 327:46–50CrossRefPubMedGoogle Scholar
  33. Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong C-X (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 132:1820–1832CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lynes EM, Simmen T (2011) Urban planning of the endoplasmic reticulum (ER): how diverse mechanisms segregate the many functions of the ER. Biochim Biophys Acta 1813:1893–1905CrossRefPubMedGoogle Scholar
  35. Marquer C, Laine J, Dauphinot L, Hanbouch L, Lemercier-Neuillet C, Pierrot N, Bossers K, Le M, Corlier F, Benstaali C et al (2014) Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes. Mol Neurodegen 9:60CrossRefGoogle Scholar
  36. Mattson MP (2010) ER calcium and Alzheimer’s disease: in a state of flux. Sci Signal 3:pe10Google Scholar
  37. Mendes CC, Gomes DA, Thompson M, Souto NC, Goes TS, Goes AM, Rodrigues MA, Gomez MV, Nathanson MH, Leite MF (2005) The type III inositol 1,4,5-trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria. J Biol Chem 280:40892–40900CrossRefPubMedGoogle Scholar
  38. Newman M, Wilson L, Verdile G, Lim A, Khan I, Moussavi Nik SH, Pursglove S, Chapman G, Martins RN, Lardelli M (2014) Differential, dominant activation and inhibition of Notch signalling and APP cleavage by truncations of PSEN1 in human disease. Hum Mol Genet 23:602–617CrossRefPubMedGoogle Scholar
  39. Patergnani S, Suski JM, Agnoletto C, Bononi A, Bonora M, De Marchi E, Giorgi C, Marchi S, Missiroli S, Poletti F et al (2011) Calcium signaling around mitochondria associated membranes (MAMs). Cell Commun Signal 9:19CrossRefPubMedPubMedCentralGoogle Scholar
  40. Peterson C, Goldman JE (1986) Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors. Proc Natl Acad Sci USA 83:2758–2762CrossRefPubMedPubMedCentralGoogle Scholar
  41. Pettegrew JW, Panchalingam K, Hamilton RL, McClure RJ (2001) Brain membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res 26:771–782CrossRefPubMedGoogle Scholar
  42. Poston CN, Krishnan SC, Bazemore-Walker CR (2013) In-depth proteomic analysis of mammalian mitochondria-associated membranes (MAM). J Proteomics 79:219–230CrossRefPubMedGoogle Scholar
  43. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. New Eng J Med 362:329–344CrossRefPubMedGoogle Scholar
  44. Raturi A, Simmen T (2013) Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM). Biochim Biophys Acta 1833:213–224CrossRefPubMedGoogle Scholar
  45. Reitz C (2012) Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis 2012:369808PubMedPubMedCentralGoogle Scholar
  46. Riemer J, Kins S (2013) Axonal transport and mitochondrial dysfunction in Alzheimer’s disease. Neurodegen Dis 12:111–124CrossRefGoogle Scholar
  47. Rohrbough J, Broadie K (2005) Lipid regulation of the synaptic vesicle cycle. Nat Rev Neurosci 6:139–150CrossRefPubMedGoogle Scholar
  48. Rusinol AE, Cui Z, Chen MH, Vance JE (1994) A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins. J Biol Chem 269:27494–27502PubMedGoogle Scholar
  49. Sala-Vila A, Navarro-Lerida I, Sanchez-Alvarez M, Bosch M, Calvo C, Lopez JA, Calvo E, Ferguson C, Giacomello M, Serafini A et al (2016) Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice. Sci Rep 6:27351CrossRefPubMedPubMedCentralGoogle Scholar
  50. Schon EA, Area-Gomez E (2010) Is Alzheimer’s disease a disorder of mitochondria-associated membranes? J Alzheimers Dis 20:S281–S292CrossRefPubMedGoogle Scholar
  51. Schon EA, Area-Gomez E (2013) Mitochondria-associated ER membranes in Alzheimer disease. Mol Cell Neurosci 55:26–36CrossRefPubMedGoogle Scholar
  52. Schreiner B, Hedskog L, Wiehager B, Ankarcrona M (2015) Amyloid-β peptides are generated in mitochondria-associated endoplasmic reticulum membranes. J Alzheimers Dis 43:369–374PubMedGoogle Scholar
  53. Selkoe DJ (2011) Alzheimer’s disease. Cold Spring Harb Perspect Biol 3:a004457CrossRefPubMedPubMedCentralGoogle Scholar
  54. Simmen T, Aslan JE, Blagoveshchenskaya AD, Thomas L, Wan L, Xiang Y, Feliciangeli SF, Hung CH, Crump CM, Thomas G (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24:717–729CrossRefPubMedPubMedCentralGoogle Scholar
  55. Sims NR, Finegan JM, Blass JP (1987) Altered metabolic properties of cultured skin fibroblasts in Alzheimer’s disease. Ann Neurol 21:451–457CrossRefPubMedGoogle Scholar
  56. Stefani M, Liguri G (2009) Cholesterol in Alzheimer’s disease: unresolved questions. Curr Alz Res 6:15–29CrossRefGoogle Scholar
  57. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U et al (2015) Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nat Genet 47:445–447CrossRefPubMedGoogle Scholar
  58. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS et al (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288CrossRefPubMedGoogle Scholar
  59. Stone SJ, Vance JE (2000) Phosphatidylserine synthase-1 and -2 are localized to mitochondria-associated membranes. J Biol Chem 275:34534–34540CrossRefPubMedGoogle Scholar
  60. Sun S, Zhang H, Liu J, Popugaeva E, Xu N-J, Feske S, White CL 3rd, Bezprozvanny I (2014) Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron 82:79–93CrossRefPubMedPubMedCentralGoogle Scholar
  61. Supnet C, Bezprozvanny I (2010) Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer’s disease. J Alzheimers Dis 20:S487–S498CrossRefPubMedPubMedCentralGoogle Scholar
  62. Szabadkai G, Bianchi K, Varnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T, Rizzuto R (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175:901–911CrossRefPubMedPubMedCentralGoogle Scholar
  63. Tambini MD, Pera M, Kanter E, Yang H, Guardia-Laguarta C, Holtzman D, Sulzer D, Area-Gomez E, Schon EA (2016) ApoE4 upregulates the activity of mitochondria-associated ER membranes. EMBO Rep 17:27–36CrossRefPubMedGoogle Scholar
  64. Vance JE (2014) MAM (mitochondria-associated membranes) in mammalian cells: Lipids and beyond. Biochim Biophys Acta 1841:595–609CrossRefPubMedGoogle Scholar
  65. Vance DE, Walkey CJ, Cui Z (1997) Phosphatidylethanolamine N-methyltransferase from liver. Biochim Biophys Acta 1348:142–150CrossRefPubMedGoogle Scholar
  66. Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G (2004) Association of γ-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem 279:44945–44954CrossRefPubMedPubMedCentralGoogle Scholar
  67. Vieira FS, Correa G, Einicker-Lamas M, Coutinho-Silva R (2010) Host-cell lipid rafts: a safe door for micro-organisms? Biol Cell 102:391–407CrossRefPubMedGoogle Scholar
  68. Walter J, Capell A, Grunberg J, Pesold B, Schindzielorz A, Prior R, Podlisny MB, Fraser P, Hyslop PS, Selkoe DJ et al (1996) The Alzheimer’s disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol Med 2:673–691PubMedPubMedCentralGoogle Scholar
  69. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X (2008) Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323CrossRefPubMedPubMedCentralGoogle Scholar
  70. Wang X, Su B, Zheng L, Perry G, Smith MA, Zhu X (2009) The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease. J Neurochem 109:153–159CrossRefPubMedPubMedCentralGoogle Scholar
  71. Wollmer MA (2010) Cholesterol-related genes in Alzheimer’s disease. Biochim Biophys Acta 1801:762–773CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of NeurologyColumbia University Medical CenterNew YorkUSA
  2. 2.Department of Genetics and DevelopmentColumbia University Medical CenterNew YorkUSA

Personalised recommendations