Skip to main content

Advertisement

SpringerLink
Log in

An Integrative Overview of Non-Amyloid and Non-Tau Pathologies in Alzheimer’s Disease

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that devastates the lives of its victims, and challenges the family members and health care infrastructures that care for them. Clinically, attempts to understand AD have focused on trying to predict the presence of, and more recently demonstrate the presence of, its characteristic amyloid plaque and neurofibrillary tangle pathologies. Fundamental research has also traditionally focused on understanding the generation, content, and pathogenicity of plaques and tangles, but in addition to this there is now an emerging independent interest in other molecular phenomena including apolipoprotein E, lipid metabolism, neuroinflammation, and mitochondrial function. While studies emphasizing the role of these phenomena have provided valuable AD insights, it is interesting that at the molecular level these entities extensively intertwine and interact. In this review, we provide a brief overview of why apolipoprotein E, lipid metabolism, neuroinflammation, and mitochondrial research have become increasingly ascendant in the AD research field, and present the case for studying these phenomena from an integrated perspective.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344. https://doi.org/10.1056/NEJMra0909142

    Article  CAS  PubMed  Google Scholar 

  2. Thies W, Bleiler L (2011) 2011 Alzheimer’s disease facts and figures. Alzheimers Dement 7(2):208–244. https://doi.org/10.1016/j.jalz.2011.02.004

    Article  Google Scholar 

  3. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA (2003) Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 60(8):1119–1122. https://doi.org/10.1001/archneur.60.8.1119

    Article  PubMed  Google Scholar 

  4. Swerdlow RH (2007) Is aging part of Alzheimer’s disease, or is Alzheimer’s disease part of aging? Neurobiol Aging 28(10):1465–1480. https://doi.org/10.1016/j.neurobiolaging.2006.06.021

    Article  PubMed  Google Scholar 

  5. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9(1):119–128. https://doi.org/10.1016/S1474-4422(09)70299-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Alzheimer A (1907) Uber eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiat Psych-Gerichtl Med 64:146–148

    Google Scholar 

  7. Alzheimer A (1911) Uber eigenartige Krankheitsfalle des spateren Alters. Z die Gesamte Neurologie Pscyhiatrie 4:456–485

    Google Scholar 

  8. Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH (1984) Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res 25(12):1277–1294

    CAS  PubMed  Google Scholar 

  9. Elshourbagy NA, Liao WS, Mahley RW, Taylor JM (1985) Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proc Natl Acad Sci USA 82(1):203–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mahley RW, Huang Y (2012) Apolipoprotein e sets the stage: response to injury triggers neuropathology. Neuron 76(5):871–885. https://doi.org/10.1016/j.neuron.2012.11.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pitas RE, Boyles JK, Lee SH, Foss D, Mahley RW (1987) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta 917(1):148–161

    Article  CAS  PubMed  Google Scholar 

  12. 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(3):a006312. https://doi.org/10.1101/cshperspect.a006312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118. https://doi.org/10.1038/nrneurol.2012.263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, Billis K, Cummins C, Gall A, Giron CG, Gil L, Gordon L, Haggerty L, Haskell E, Hourlier T, Izuogu OG, Janacek SH, Juettemann T, To JK, Laird MR, Lavidas I, Liu Z, Loveland JE, Maurel T, McLaren W, Moore B, Mudge J, Murphy DN, Newman V, Nuhn M, Ogeh D, Ong CK, Parker A, Patricio M, Riat HS, Schuilenburg H, Sheppard D, Sparrow H, Taylor K, Thormann A, Vullo A, Walts B, Zadissa A, Frankish A, Hunt SE, Kostadima M, Langridge N, Martin FJ, Muffato M, Perry E, Ruffier M, Staines DM, Trevanion SJ, Aken BL, Cunningham F, Yates A, Flicek P (2018) Ensembl 2018. Nucleic Acids Res 46(D1):D754–D761. https://doi.org/10.1093/nar/gkx1098

    Article  CAS  PubMed  Google Scholar 

  15. Fullerton SM, Clark AG, Weiss KM, Nickerson DA, Taylor SL, Stengard JH, Salomaa V, Vartiainen E, Perola M, Boerwinkle E, Sing CF (2000) Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet 67(4):881–900. https://doi.org/10.1086/303070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Eisenberg DT, Kuzawa CW, Hayes MG (2010) Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. Am J Phys Anthropol 143(1):100–111. https://doi.org/10.1002/ajpa.21298

    Article  PubMed  Google Scholar 

  17. Wetterau JR, Aggerbeck LP, Rall SC Jr, Weisgraber KH (1988) Human apolipoprotein E3 in aqueous solution. I. Evidence for two structural domains. J Biol Chem 263(13):6240–6248

    CAS  PubMed  Google Scholar 

  18. Mizuguchi C, Hata M, Dhanasekaran P, Nickel M, Okuhira K, Phillips MC, Lund-Katz S, Saito H (2014) Fluorescence study of domain structure and lipid interaction of human apolipoproteins E3 and E4. Biochim Biophys Acta 1841(12):1716–1724. https://doi.org/10.1016/j.bbalip.2014.09.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Morrow JA, Segall ML, Lund-Katz S, Phillips MC, Knapp M, Rupp B, Weisgraber KH (2000) Differences in stability among the human apolipoprotein E isoforms determined by the amino-terminal domain. Biochemistry 39(38):11657–11666

    Article  CAS  PubMed  Google Scholar 

  20. Ramaswamy G, Xu Q, Huang Y, Weisgraber KH (2005) Effect of domain interaction on apolipoprotein E levels in mouse brain. J Neurosci 25(46):10658–10663. https://doi.org/10.1523/JNEUROSCI.1922-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hatters DM, Peters-Libeu CA, Weisgraber KH (2006) Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445–454. https://doi.org/10.1016/j.tibs.2006.06.008

    Article  CAS  PubMed  Google Scholar 

  22. Aoki K, Uchihara T, Sanjo N, Nakamura A, Ikeda K, Tsuchiya K, Wakayama Y (2003) Increased expression of neuronal apolipoprotein E in human brain with cerebral infarction. Stroke 34(4):875–880. https://doi.org/10.1161/01.STR.0000064320.73388.C6

    Article  CAS  PubMed  Google Scholar 

  23. Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E, Hopkins PC, Scearce-Levie K, Weisgraber KH, Mucke L, Mahley RW, Huang Y (2003) Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci USA 100(19):10966–10971. https://doi.org/10.1073/pnas.1434398100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nakamura T, Watanabe A, Fujino T, Hosono T, Michikawa M (2009) Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol Neurodegener 4:35. https://doi.org/10.1186/1750-1326-4-35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW (2001) Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci USA 98(15):8838–8843. https://doi.org/10.1073/pnas.151254698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rohn TT, Catlin LW, Coonse KG, Habig JW (2012) Identification of an amino-terminal fragment of apolipoprotein E4 that localizes to neurofibrillary tangles of the Alzheimer’s disease brain. Brain Res 1475:106–115. https://doi.org/10.1016/j.brainres.2012.08.003

    Article  CAS  PubMed  Google Scholar 

  27. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90(5):1977–1981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923

    Article  CAS  PubMed  Google Scholar 

  29. Conejero-Goldberg C, Gomar JJ, Bobes-Bascaran T, Hyde TM, Kleinman JE, Herman MM, Chen S, Davies P, Goldberg TE (2014) APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms. Mol Psychiatry 19(11):1243–1250. https://doi.org/10.1038/mp.2013.194

    Article  CAS  PubMed  Google Scholar 

  30. Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genom Hum Genet 1:507–537. https://doi.org/10.1146/annurev.genom.1.1.507

    Article  CAS  Google Scholar 

  31. Koffie RM, Hashimoto T, Tai HC, Kay KR, Serrano-Pozo A, Joyner D, Hou S, Kopeikina KJ, Frosch MP, Lee VM, Holtzman DM, Hyman BT, Spires-Jones TL (2012) Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-beta. Brain 135(Pt 7):2155–2168. https://doi.org/10.1093/brain/aws127

    Article  PubMed  PubMed Central  Google Scholar 

  32. Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Investig 118(12):4002–4013. https://doi.org/10.1172/JCI36663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat 8(6):429–431. https://doi.org/10.1002/ca.980080612

    Article  CAS  PubMed  Google Scholar 

  34. Grosgen S, Grimm MO, Friess P, Hartmann T (2010) Role of amyloid beta in lipid homeostasis. Biochim Biophys Acta 1801(8):966–974. https://doi.org/10.1016/j.bbalip.2010.05.002

    Article  CAS  PubMed  Google Scholar 

  35. Dietschy JM, Turley SD (2001) Cholesterol metabolism in the brain. Curr Opin Lipidol 12(2):105–112

    Article  CAS  PubMed  Google Scholar 

  36. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O’Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093. https://doi.org/10.1038/ng.440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fievet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, European Alzheimer’s Disease Initiative I, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossu P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanche H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alperovitch A, Lathrop M, Amouyel P (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10):1094–1099. https://doi.org/10.1038/ng.439

    Article  CAS  PubMed  Google Scholar 

  38. Jones SE, Jomary C (2002) Clusterin. Int J Biochem Cell Biol 34(5):427–431

    Article  CAS  PubMed  Google Scholar 

  39. Calero M, Rostagno A, Matsubara E, Zlokovic B, Frangione B, Ghiso J (2000) Apolipoprotein J (clusterin) and Alzheimer’s disease. Microsc Res Tech 50 (4):305–315. https://doi.org/10.1002/1097-0029(20000815)50:4%3C305::AID-JEMT10%3E3.0.CO;2-L

    Article  CAS  PubMed  Google Scholar 

  40. Glennon EB, Whitehouse IJ, Miners JS, Kehoe PG, Love S, Kellett KA, Hooper NM (2013) BIN1 is decreased in sporadic but not familial Alzheimer’s disease or in aging. PLoS ONE 8(10):e78806. https://doi.org/10.1371/journal.pone.0078806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Ruther E, Schurmann B, Heun R, Kolsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Gallacher J, Hull M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, Alzheimer’s Disease Neuroimaging I, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, consortium C, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alperovitch A, Lathrop M, consortium E, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snaedal J, Bjornsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossu P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O’Donovan M, Amouyel P, Williams J (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43(5):429–435. https://doi.org/10.1038/ng.803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Villegas-Llerena C, Phillips A, Garcia-Reitboeck P, Hardy J, Pocock JM (2016) Microglial genes regulating neuroinflammation in the progression of Alzheimer’s disease. Curr Opin Neurobiol 36:74–81. https://doi.org/10.1016/j.conb.2015.10.004

    Article  CAS  PubMed  Google Scholar 

  43. Martin V, Fabelo N, Santpere G, Puig B, Marin R, Ferrer I, Diaz M (2010) Lipid alterations in lipid rafts from Alzheimer’s disease human brain cortex. J Alzheimers Dis 19(2):489–502. https://doi.org/10.3233/JAD-2010-1242

    Article  CAS  PubMed  Google Scholar 

  44. Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA (2009) Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement Geriatr Cogn Disord 28(1):75–80. https://doi.org/10.1159/000231980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S (2014) Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Med 12:51. https://doi.org/10.1186/1741-7015-12-51

    Article  PubMed  PubMed Central  Google Scholar 

  46. Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS (2011) A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 77(6):556–563. https://doi.org/10.1212/WNL.0b013e318228bf11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jurevics H, Morell P (1995) Cholesterol for synthesis of myelin is made locally, not imported into brain. J Neurochem 64(2):895–901

    Article  CAS  PubMed  Google Scholar 

  48. Zarate R, El Jaber-Vazdekis N, Tejera N, Perez JA, Rodriguez C (2017) Significance of long chain polyunsaturated fatty acids in human health. Clin Transl Med 6(1):25. https://doi.org/10.1186/s40169-017-0153-6

    Article  PubMed  PubMed Central  Google Scholar 

  49. Cole GM, Ma QL, Frautschy SA (2009) Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids 81(2–3):213–221. https://doi.org/10.1016/j.plefa.2009.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mergenthaler P, Lindauer U, Dienel GA, Meisel A (2013) Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 36(10):587–597. https://doi.org/10.1016/j.tins.2013.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Edmond J, Robbins RA, Bergstrom JD, Cole RA, de Vellis J (1987) Capacity for substrate utilization in oxidative metabolism by neurons, astrocytes, and oligodendrocytes from developing brain in primary culture. J Neurosci Res 18(4):551–561. https://doi.org/10.1002/jnr.490180407

    Article  CAS  PubMed  Google Scholar 

  52. Tracey TJ, Steyn FJ, Wolvetang EJ, Ngo ST (2018) Neuronal lipid metabolism: multiple pathways driving functional outcomes in health and disease. Front Mol Neurosci 11:10. https://doi.org/10.3389/fnmol.2018.00010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Guzman M, Blazquez C (2001) Is there an astrocyte-neuron ketone body shuttle? Trends in endocrinology and metabolism. TEM 12(4):169–173

    CAS  PubMed  Google Scholar 

  54. Garcia-Canaveras JC, Peris-Diaz MD, Alcoriza-Balaguer MI, Cerdan-Calero M, Donato MT, Lahoz A (2017) A lipidomic cell-based assay for studying drug-induced phospholipidosis and steatosis. Electrophoresis 38(18):2331–2340. https://doi.org/10.1002/elps.201700079

    Article  CAS  PubMed  Google Scholar 

  55. Lydic TA, Goo YH (2018) Lipidomics unveils the complexity of the lipidome in metabolic diseases. Clin Transl Med 7(1):4. https://doi.org/10.1186/s40169-018-0182-9

    Article  PubMed  PubMed Central  Google Scholar 

  56. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405. https://doi.org/10.1016/S1474-4422(15)70016-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shi FD (2015) Neuroinflammation. Neurosci Bull 31(6):714–716. https://doi.org/10.1007/s12264-015-1568-y

    Article  PubMed  PubMed Central  Google Scholar 

  58. Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19(12):1584–1596. https://doi.org/10.1038/nm.3407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA (2010) Neuroinflammation—an early event in both the history and pathogenesis of Alzheimer’s disease. Neurodegener Dis 7(1–3):38–41. https://doi.org/10.1159/000283480

    Article  CAS  PubMed  Google Scholar 

  60. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Moron FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fievet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossu P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer’s Disease I, Genetic, Environmental Risk in Alzheimer’s D, Alzheimer’s Disease Genetic C, Cohorts for H, Aging Research in Genomic E, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannefelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O’Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley Jr. TH, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltuenen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nothen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45(12):1452–1458. https://doi.org/10.1038/ng.2802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wilkins HM, Carl SM, Greenlief AC, Festoff BW, Swerdlow RH (2014) Bioenergetic dysfunction and inflammation in Alzheimer’s disease: a possible connection. Front Aging Neurosci 6:311. https://doi.org/10.3389/fnagi.2014.00311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, Li X, Rademakers R, Kang SS, Xu H, Younkin S, Das P, Fryer JD, Bu G (2015) Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem 290(43):26043–26050. https://doi.org/10.1074/jbc.M115.679043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Karch CM, Goate AM (2015) Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77(1):43–51. https://doi.org/10.1016/j.biopsych.2014.05.006

    Article  CAS  PubMed  Google Scholar 

  64. Hollenbach JA, Oksenberg JR (2015) The immunogenetics of multiple sclerosis: a comprehensive review. J Autoimmun 64:13–25. https://doi.org/10.1016/j.jaut.2015.06.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28(1):12–18. https://doi.org/10.1016/j.it.2006.11.004

    Article  CAS  PubMed  Google Scholar 

  66. Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6(4):193–201. https://doi.org/10.1038/nrneurol.2010.17

    Article  PubMed  Google Scholar 

  67. Block ML (2008) NADPH oxidase as a therapeutic target in Alzheimer’s disease. BMC Neurosci 9(Suppl 2):S8. https://doi.org/10.1186/1471-2202-9-S2-S8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Smith JA, Das A, Ray SK, Banik NL (2012) Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 87(1):10–20. https://doi.org/10.1016/j.brainresbull.2011.10.004

    Article  CAS  PubMed  Google Scholar 

  69. Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77(1):10–18. https://doi.org/10.1016/j.neuron.2012.12.023

    Article  CAS  PubMed  Google Scholar 

  70. Perry VH, O’Connor V (2010) The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective. ASN Neuro 2(5):e00047. https://doi.org/10.1042/AN20100024

    Article  PubMed  Google Scholar 

  71. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27(5):457–464. https://doi.org/10.1002/ana.410270502

    Article  CAS  PubMed  Google Scholar 

  72. Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12(9):623–635. https://doi.org/10.1038/nri3265

    Article  CAS  PubMed  Google Scholar 

  73. Marques F, Sousa JC, Sousa N, Palha JA (2013) Blood-brain-barriers in aging and in Alzheimer’s disease. Mol Neurodegener 8:38. https://doi.org/10.1186/1750-1326-8-38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hennessy E, Griffin EW, Cunningham C (2015) Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1beta and TNF-alpha. J Neurosci 35(22):8411–8422. https://doi.org/10.1523/JNEUROSCI.2745-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hales KG (2004) The machinery of mitochondrial fusion, division, and distribution, and emerging connections to apoptosis. Mitochondrion 4(4):285–308. https://doi.org/10.1016/j.mito.2004.05.007

    Article  CAS  PubMed  Google Scholar 

  76. Amiri M, Hollenbeck PJ (2008) Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev Neurobiol 68(11):1348–1361. https://doi.org/10.1002/dneu.20668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL (2014) Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 206(5):655–670. https://doi.org/10.1083/jcb.201401070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Swerdlow RH (2009) The neurodegenerative mitochondriopathies. J Alzheimers Dis 17(4):737–751. https://doi.org/10.3233/JAD-2009-1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Swerdlow RH (2011) Brain aging, Alzheimer’s disease, and mitochondria. Biochim Biophys Acta 1812(12):1630–1639. https://doi.org/10.1016/j.bbadis.2011.08.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Swerdlow RH, Koppel S, Weidling I, Hayley C, Ji Y, Wilkins HM (2017) Mitochondria, cybrids, aging, and Alzheimer’s disease. Progress in molecular biology translational science 146:259–302. https://doi.org/10.1016/bs.pmbts.2016.12.017

    Article  CAS  PubMed  Google Scholar 

  81. Wallace DC (1992) Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256(5057):628–632

    Article  CAS  PubMed  Google Scholar 

  82. Breuer ME, Koopman WJ, Koene S, Nooteboom M, Rodenburg RJ, Willems PH, Smeitink JA (2013) The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases. Neurobiol Dis 51:27–34. https://doi.org/10.1016/j.nbd.2012.03.007

    Article  CAS  PubMed  Google Scholar 

  83. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795. https://doi.org/10.1038/nature05292

    Article  CAS  PubMed  Google Scholar 

  84. Swerdlow RH, Khan SM (2004) A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses 63(1):8–20. https://doi.org/10.1016/j.mehy.2003.12.045

    Article  CAS  PubMed  Google Scholar 

  85. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–R462. https://doi.org/10.1016/j.cub.2014.03.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Good PF, Werner P, Hsu A, Olanow CW, Perl DP (1996) Evidence of neuronal oxidative damage in Alzheimer’s disease. Am J Pathol 149(1):21–28

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Hamanaka H, Katoh-Fukui Y, Suzuki K, Kobayashi M, Suzuki R, Motegi Y, Nakahara Y, Takeshita A, Kawai M, Ishiguro K, Yokoyama M, Fujita SC (2000) Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice. Hum Mol Genet 9(3):353–361

    Article  CAS  PubMed  Google Scholar 

  88. Hayashi H, Igbavboa U, Hamanaka H, Kobayashi M, Fujita SC, Wood WG, Yanagisawa K (2002) Cholesterol is increased in the exofacial leaflet of synaptic plasma membranes of human apolipoprotein E4 knock-in mice. Neuroreport 13(4):383–386

    Article  CAS  PubMed  Google Scholar 

  89. Cossec JC, Marquer C, Panchal M, Lazar AN, Duyckaerts C, Potier MC (2010) Cholesterol changes in Alzheimer’s disease: methods of analysis and impact on the formation of enlarged endosomes. Biochim Biophys Acta 1801(8):839–845. https://doi.org/10.1016/j.bbalip.2010.03.010

    Article  CAS  PubMed  Google Scholar 

  90. Chen HK, Ji ZS, Dodson SE, Miranda RD, Rosenblum CI, Reynolds IJ, Freedman SB, Weisgraber KH, Huang Y, Mahley RW (2011) Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease. J Biol Chem 286(7):5215–5221. https://doi.org/10.1074/jbc.M110.151084

    Article  CAS  PubMed  Google Scholar 

  91. Coppack SW (2001) Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60(3):349–356

    Article  CAS  PubMed  Google Scholar 

  92. Ogawa H, Nielsen S, Kawakami M (1989) Cachectin/tumor necrosis factor and interleukin-1 show different modes of combined effect on lipoprotein lipase activity and intracellular lipolysis in 3T3-L1 cells. Biochim Biophys Acta 1003(2):131–135

    Article  CAS  PubMed  Google Scholar 

  93. Klosinski LP, Yao J, Yin F, Fonteh AN, Harrington MG, Christensen TA, Trushina E, Brinton RD (2015) White matter lipids as a ketogenic fuel supply in aging female brain: implications for Alzheimer’s disease. EBioMedicine 2(12):1888–1904. https://doi.org/10.1016/j.ebiom.2015.11.002

    Article  PubMed  PubMed Central  Google Scholar 

  94. Aleong R, Blain JF, Poirier J (2008) Pro-inflammatory cytokines modulate glial apolipoprotein E secretion. Curr Alzheimer Res 5(1):33–37

    Article  CAS  PubMed  Google Scholar 

  95. Ophir G, Amariglio N, Jacob-Hirsch J, Elkon R, Rechavi G, Michaelson DM (2005) Apolipoprotein E4 enhances brain inflammation by modulation of the NF-kappaB signaling cascade. Neurobiol Dis 20(3):709–718. https://doi.org/10.1016/j.nbd.2005.05.002

    Article  CAS  PubMed  Google Scholar 

  96. Pocivavsek A, Mikhailenko I, Strickland DK, Rebeck GW (2009) Microglial low-density lipoprotein receptor-related protein 1 modulates c-Jun N-terminal kinase activation. J Neuroimmunol 214(1–2):25–32. https://doi.org/10.1016/j.jneuroim.2009.06.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485(7399):512–516. https://doi.org/10.1038/nature11087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wilkins HM, Carl SM, Weber SG, Ramanujan SA, Festoff BW, Linseman DA, Swerdlow RH (2015) Mitochondrial lysates induce inflammation and Alzheimer’s disease-relevant changes in microglial and neuronal cells. J Alzheimers Dis 45(1):305–318. https://doi.org/10.3233/JAD-142334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Motori E, Puyal J, Toni N, Ghanem A, Angeloni C, Malaguti M, Cantelli-Forti G, Berninger B, Conzelmann KK, Gotz M, Winklhofer KF, Hrelia S, Bergami M (2013) Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab 18(6):844–859. https://doi.org/10.1016/j.cmet.2013.11.005

    Article  CAS  PubMed  Google Scholar 

  100. Scheffler IE (2008) Mitochondria, 2nd edn. Wiley-Liss, Hoboken

    Google Scholar 

  101. Button EB, Mitchell AS, Domingos MM, Chung JH, Bradley RM, Hashemi A, Marvyn PM, Patterson AC, Stark KD, Quadrilatero J, Duncan RE (2014) Microglial cell activation increases saturated and decreases monounsaturated fatty acid content, but both lipid species are proinflammatory. Lipids 49(4):305–316. https://doi.org/10.1007/s11745-014-3882-y

    Article  CAS  PubMed  Google Scholar 

  102. Gafencu AV, Robciuc MR, Fuior E, Zannis VI, Kardassis D, Simionescu M (2007) Inflammatory signaling pathways regulating ApoE gene expression in macrophages. J Biol Chem 282(30):21776–21785. https://doi.org/10.1074/jbc.M611422200

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported by the University of Kansas Alzheimer’s Disease Center (NIA P30AG035982).

Author information

Authors and Affiliations

  1. University of Kansas Alzheimer’s Disease Center, Fairway, KS, USA

    Blaise W. Menta & Russell H. Swerdlow

  2. Neuroscience Graduate Program, University of Kansas Medical Center, Lawrence, KS, USA

    Blaise W. Menta & Russell H. Swerdlow

  3. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Lawrence, KS, USA

    Blaise W. Menta & Russell H. Swerdlow

  4. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Lawrence, KS, USA

    Russell H. Swerdlow

  5. Department of Neurology, University of Kansas Medical Center, Lawrence, KS, USA

    Russell H. Swerdlow

  6. Landon Center on Aging, MS 2012, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA

    Russell H. Swerdlow

Authors
  1. Blaise W. Menta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Russell H. Swerdlow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Russell H. Swerdlow.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Menta, B.W., Swerdlow, R.H. An Integrative Overview of Non-Amyloid and Non-Tau Pathologies in Alzheimer’s Disease. Neurochem Res 44, 12–21 (2019). https://doi.org/10.1007/s11064-018-2603-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-018-2603-y

Keywords

Search

Navigation