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Brain regional correlation of amyloid-β with synapses and apolipoprotein E in non-demented individuals: potential mechanisms underlying regional vulnerability to amyloid-β accumulation

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Abstract

To reveal the underlying mechanisms responsible for the regional vulnerability to amyloid-β (Aβ) accumulation prior to the development of Alzheimer’s disease, we studied distribution of Aβ, apolipoprotein E (apoE), synaptic markers, and other molecules involved in Aβ metabolism in multiple brain areas of non-demented individuals. Twelve brain regions including neocortical, limbic, and subcortical areas were dissected from brains of non-demented individuals and extracted according to increasing insolubility by a sequential three-step method. The levels of Aβ40, Aβ42, apoE, APP, APP-CTFβ, BACE1, presenilin-1, neprilysin, insulysin, LRP1, LDLR, synaptophysin, PSD95, GFAP, and lactate were determined by ELISAs or enzymatic assays. The regional distribution of apoE showed moderate-to-strong inverse correlation with levels of Aβ, especially insoluble Aβ40. On the other hand, the regional distributions of synaptic markers, particularly PSD95, showed moderate-to-strong positive correlation with levels of Aβ, especially soluble Aβ40. The regional correlations between Aβ and LRP1, GFAP, or lactate were mild-to-moderate. Moderate-to-strong positive regional correlations were observed between apoE and GFAP or lactate and between PSD95 and LRP1. No significant regional correlations were detected between Aβ and APP, APP-CTFβ, BACE1, or presenilin-1, those involved in Aβ production. There were no significant negative regional correlations between Aβ and two major Aβ degrading enzymes, neprilysin and insulysin. These regional correlations remained consistent regardless of the degree of Aβ accumulation. The regional vulnerability to Aβ accumulation may be due to a net balance between two competing processes: (1) synapses involved in promoting the initial Aβ accumulation and (2) astrocyte-derived apoE involved in preventing Aβ accumulation.

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References

  1. Akiyama H, Kondo H, Ikeda K, Kato M, McGeer PL (2001) Immunohistochemical localization of neprilysin in the human cerebral cortex: inverse association with vulnerability to amyloid beta-protein (Abeta) deposition. Brain Res 902:277–281

    Article  PubMed  CAS  Google Scholar 

  2. Arold S, Sullivan P, Bilousova T et al (2012) Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer’s disease and apoE TR mouse cortex. Acta Neuropathol 123:39–52

    Article  PubMed  CAS  Google Scholar 

  3. Bales KR, Liu F, Wu S et al (2009) Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci 29:6771–6779. doi:10.1523/jneurosci.0887-09.2009

    Article  PubMed  CAS  Google Scholar 

  4. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377:1019–1031. doi:10.1016/s0140-6736(10)61349-9

    Article  PubMed  Google Scholar 

  5. Benkovic SA, McGowan EM, Rothwell NJ, Hutton M, Morgan DG, Gordon MN (1997) Regional and cellular localization of presenilin-2 RNA in rat and human brain. Exp Neurol 145:555–564. doi:10.1006/exnr.1997.6487

    Article  PubMed  CAS  Google Scholar 

  6. Bernstein HG, Ansorge S, Riederer P, Reiser M, Frolich L, Bogerts B (1999) Insulin-degrading enzyme in the Alzheimer’s disease brain: prominent localization in neurons and senile plaques. Neurosci Lett 263:161–164

    Article  PubMed  CAS  Google Scholar 

  7. Bero AW, Yan P, Roh JH et al (2011) Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci 14:750–756. doi:10.1038/nn.2801

    Article  PubMed  CAS  Google Scholar 

  8. Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  PubMed  CAS  Google Scholar 

  9. Bramanti V, Tomassoni D, Avitabile M, Amenta F, Avola R (2010) Biomarkers of glial cell proliferation and differentiation in culture. Front Biosci 2:558–570

    Article  Google Scholar 

  10. Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344. doi:10.1038/nrn2620

    Article  PubMed  CAS  Google Scholar 

  11. Buckner RL, Snyder AZ, Shannon BJ et al (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25:7709–7717. doi:10.1523/jneurosci.2177-05.2005

    Article  PubMed  CAS  Google Scholar 

  12. Camus MC, Chapman MJ, Forgez P, Laplaud PM (1983) Distribution and characterization of the serum lipoproteins and apoproteins in the mouse, Mus musculus. J Lipid Res 24:1210–1228

    PubMed  CAS  Google Scholar 

  13. Chakrabarty P, Jansen-West K, Beccard A et al (2010) Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J 24:548–559. doi:10.1096/fj.09-141754

    Article  PubMed  CAS  Google Scholar 

  14. Cirrito JR, Yamada KA, Finn MB et al (2005) Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48:913–922. doi:10.1016/j.neuron.2005.10.028

    Article  PubMed  CAS  Google Scholar 

  15. De Strooper B, Vassar R, Golde T (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6:99–107

    Article  PubMed  Google Scholar 

  16. Delledonne A, Kouri N, Reinstatler L et al (2009) Development of monoclonal antibodies and quantitative ELISAs targeting insulin-degrading enzyme. Mol Neurodegener 4:39. doi:10.1186/1750-1326-4-39

    Article  PubMed  Google Scholar 

  17. Dickson DW, Crystal HA, Mattiace LA et al (1992) Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 13:179–189

    Article  PubMed  CAS  Google Scholar 

  18. Eckman EA, Adams SK, Troendle FJ et al (2006) Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme. J Biol Chem 281:30471–30478. doi:10.1074/jbc.M605827200

    Article  PubMed  CAS  Google Scholar 

  19. Fuentealba RA, Liu Q, Zhang J et al (2010) Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking. PLoS One 5:e11884. doi:10.1371/journal.pone.0011884

    Article  PubMed  Google Scholar 

  20. Goedert M (1987) Neuronal localization of amyloid beta protein precursor mRNA in normal human brain and in Alzheimer’s disease. EMBO J 6:3627–3632

    PubMed  CAS  Google Scholar 

  21. Goulinet S, Chapman MJ (1993) Plasma lipoproteins in the golden Syrian hamster (Mesocricetus auratus): heterogeneity of apoB- and apoA-I-containing particles. J Lipid Res 34:943–959

    PubMed  CAS  Google Scholar 

  22. Gupta VB, Laws SM, Villemagne VL et al (2011) Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging. Neurology 76:1091–1098

    Article  PubMed  CAS  Google Scholar 

  23. Haddy N, De Bacquer D, Chemaly MM et al (2002) The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe. Eur J Hum Genet 10:841–850

    Article  PubMed  CAS  Google Scholar 

  24. Holtzman DM, Fagan AM, Mackey B et al (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47:739–747

    Article  PubMed  CAS  Google Scholar 

  25. Iwata N, Tsubuki S, Takaki Y et al (2001) Metabolic regulation of brain Abeta by neprilysin. Science 292:1550–1552. doi:10.1126/science.1059946

    Article  PubMed  CAS  Google Scholar 

  26. Jack CR Jr, Knopman DS, Jagust WJ et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128. doi:10.1016/s1474-4422(09)70299-6

    Article  PubMed  CAS  Google Scholar 

  27. Jack CR Jr, Lowe VJ, Weigand SD et al (2009) Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain 132:1355–1365. doi:10.1093/brain/awp062

    Article  PubMed  Google Scholar 

  28. Jack CR Jr, Wiste HJ, Vemuri P et al (2010) Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain 133:3336–3348

    Article  PubMed  Google Scholar 

  29. Jiang Q, Lee CY, Mandrekar S et al (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58:681–693. doi:10.1016/j.neuron.2008.04.010

    Article  PubMed  CAS  Google Scholar 

  30. Kanekiyo T, Liu CC, Shinohara M, Li J, Bu G (2012) LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer’s amyloid-beta. J Neurosci 32:16458–16465. doi:10.1523/jneurosci.3987-12.2012

    Article  PubMed  CAS  Google Scholar 

  31. Kanekiyo T, Zhang J, Liu Q, Liu CC, Zhang L, Bu G (2011) Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake. J Neurosci 31:1644–1651. doi:10.1523/jneurosci.5491-10.2011

    Article  PubMed  CAS  Google Scholar 

  32. Kim J, Jiang H, Park S et al (2011) Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. J Neurosci 31:18007–18012. doi:10.1523/jneurosci.3773-11.2011

    Article  PubMed  CAS  Google Scholar 

  33. Klunk WE, Price JC, Mathis CA et al (2007) Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci 27:6174–6184. doi:10.1523/jneurosci.0730-07.2007

    Article  PubMed  CAS  Google Scholar 

  34. Koffie R, Hyman B, Spires-Jones T (2011) Alzheimer’s disease: synapses gone cold. Molecular Neurodegeneration 6:63

    Article  PubMed  Google Scholar 

  35. Koffie RM, Hashimoto T, Tai HC et al (2012) Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-beta. Brain 135:2155–2168

    Article  PubMed  Google Scholar 

  36. Koffie RM, Meyer-Luehmann M, Hashimoto T et al (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci USA 106:4012–4017. doi:10.1073/pnas.0811698106

    Article  PubMed  CAS  Google Scholar 

  37. Koistinaho M, Lin S, Wu X et al (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10:719–726. doi:10.1038/nm1058

    Article  PubMed  CAS  Google Scholar 

  38. Lazarov O, Lee M, Peterson DA, Sisodia SS (2002) Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci 22:9785–9793

    PubMed  CAS  Google Scholar 

  39. Leissring MA, Farris W, Chang AY et al (2003) Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40:1087–1093

    Article  PubMed  CAS  Google Scholar 

  40. Marquez-Sterling NR, Lo AC, Sisodia SS, Koo EH (1997) Trafficking of cell-surface beta-amyloid precursor protein: evidence that a sorting intermediate participates in synaptic vesicle recycling. J Neurosci 17:140–151

    PubMed  CAS  Google Scholar 

  41. May P, Rohlmann A, Bock HH et al (2004) Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. Mol Cell Biol 24:8872–8883. doi:10.1128/mcb.24.20.8872-8883.2004

    Article  PubMed  CAS  Google Scholar 

  42. Meilandt WJ, Cisse M, Ho K et al (2009) Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice. J Neurosci 29:1977–1986. doi:10.1523/jneurosci.2984-08.2009

    Article  PubMed  CAS  Google Scholar 

  43. Miller BC, Eckman EA, Sambamurti K et al (2003) Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci USA 100:6221–6226. doi:10.1073/pnas.1031520100

    Article  PubMed  CAS  Google Scholar 

  44. Mooijaart SP, Berbee JF, van Heemst D et al (2006) ApoE plasma levels and risk of cardiovascular mortality in old age. PLoS Med 3:9

    Article  Google Scholar 

  45. Moore AH, O’Banion MK (2002) Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease. Adv Drug Deliv Rev 54:1627–1656

    Article  PubMed  CAS  Google Scholar 

  46. Moore BD, Chakrabarty P, Levites Y et al (2012) Overlapping profiles of Abeta peptides in the Alzheimer’s disease and pathological aging brains. Alzheimers Res Ther 4(3):18

    Article  PubMed  CAS  Google Scholar 

  47. Morris JC, Roe CM, Xiong C et al (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 67:122–131. doi:10.1002/ana.21843

    Article  PubMed  CAS  Google Scholar 

  48. Nalivaeva NN, Beckett C, Belyaev ND, Turner AJ (2012) Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease? J Neurochem 1:167–185

    Article  Google Scholar 

  49. Okello A, Koivunen J, Edison P et al (2009) Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 73:754–760

    Article  PubMed  CAS  Google Scholar 

  50. Page K, Hollister R, Tanzi RE, Hyman BT (1996) In situ hybridization analysis of presenilin 1 mRNA in Alzheimer disease and in lesioned rat brain. Proc Natl Acad Sci USA 93:14020–14024

    Article  PubMed  CAS  Google Scholar 

  51. Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 91:10625–10629

    Article  PubMed  CAS  Google Scholar 

  52. Pocivavsek A, Burns MP, Rebeck GW (2009) Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase. Glia 57:444–453. doi:10.1002/glia.20772

    Article  PubMed  Google Scholar 

  53. Reiman EM, Chen K, Liu X et al (2009) Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA 106:6820–6825. doi:10.1073/pnas.0900345106

    Article  PubMed  CAS  Google Scholar 

  54. Riddell DR, Zhou H, Atchison K et al (2008) Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci 28:11445–11453

    Article  PubMed  CAS  Google Scholar 

  55. Shankar GM, Li S, Mehta TH et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842. doi:10.1038/nm1782

    Article  PubMed  CAS  Google Scholar 

  56. Shibata M, Yamada S, Kumar SR et al (2000) Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106:1489–1499. doi:10.1172/jci10498

    Article  PubMed  CAS  Google Scholar 

  57. Shigematsu K, McGeer PL, McGeer EG (1992) Localization of amyloid precursor protein in selective postsynaptic densities of rat cortical neurons. Brain Res 592:353–357

    Article  PubMed  CAS  Google Scholar 

  58. Sokolow S, Luu SH, Nandy K et al (2012) Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer’s disease cortex. Neurobiol Dis 45:381–387

    Article  PubMed  CAS  Google Scholar 

  59. Suh J, Lyckman A, Wang L, Eckman EA, Guenette SY (2011) FE65 proteins regulate NMDA receptor activation-induced amyloid precursor protein processing. J Neurochem 119:377–388

    Article  PubMed  CAS  Google Scholar 

  60. Sullivan PM, Han B, Liu F et al (2011) Reduced levels of human apoE4 protein in an animal model of cognitive impairment. Neurobiol Aging 32:791–801

    Article  PubMed  CAS  Google Scholar 

  61. Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879

    Article  PubMed  CAS  Google Scholar 

  62. Takami K, Terai K, Matsuo A, Walker DG, McGeer PL (1997) Expression of presenilin-1 and -2 mRNAs in rat and Alzheimer’s disease brains. Brain Res 748:122–130

    Article  PubMed  CAS  Google Scholar 

  63. Thal DR (2012) The role of astrocytes in amyloid beta-protein toxicity and clearance. Exp Neurol 236:1–5

    Article  PubMed  CAS  Google Scholar 

  64. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    Article  PubMed  Google Scholar 

  65. Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283:29615–29619. doi:10.1074/jbc.R800019200

    Article  PubMed  CAS  Google Scholar 

  66. Vassar R, Bennett BD, Babu-Khan S et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741

    Article  PubMed  CAS  Google Scholar 

  67. Verges DK, Restivo JL, Goebel WD, Holtzman DM, Cirrito JR (2011) Opposing synaptic regulation of amyloid-beta metabolism by NMDA receptors in vivo. J Neurosci 31:11328–11337

    Article  PubMed  CAS  Google Scholar 

  68. Villemagne VL, Ataka S, Mizuno T et al (2009) High striatal amyloid beta-peptide deposition across different autosomal Alzheimer disease mutation types. Arch Neurol 66:1537–1544. doi:10.1001/archneurol.2009.285

    Article  PubMed  Google Scholar 

  69. Villemagne VL, Pike KE, Chetelat G et al (2011) Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 69:181–192

    Article  PubMed  CAS  Google Scholar 

  70. Vlassenko AG, Vaishnavi SN, Couture L et al (2010) Spatial correlation between brain aerobic glycolysis and amyloid-beta (Abeta) deposition. Proc Natl Acad Sci USA 107:17763–17767. doi:10.1073/pnas.1010461107

    Article  PubMed  CAS  Google Scholar 

  71. Wenk GL (2003) Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry 9:7–10

    Google Scholar 

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Acknowledgments

We thank Dr. Pritam Das for ELISA reagents detecting Aβ and an antibody against C-terminus region of APP, Drs. Malcolm Leissring and Samir Abdul-Hay for ELISA reagents detecting IDE, Mr. John Gonzalez for assisting with dissection of brain tissues, Ms. Caroline Stetler for careful reading of this manuscript, and Dr. Takahisa Kanekiyo for helpful discussion. This research was supported by grants from the National Institutes of Health (NIH) (P01 AG030128-Project 3 & P01 NS074969-Project 3 to G.B.); Alzheimer’s Drug Discovery Foundation (ADDF) (to G.B.); American Health Assistance Foundation (AHAF) (to G.B.); Mayo Clinic Alzheimer’s Disease Research Center (ADRC) (P50 AG016574) (to D.W.D and M.S.); Japan Heart Foundation and Naito Foundation (to M.S.). The authors also acknowledge the many individuals who contribute to the Mayo Clinic Alzheimer Disease Research Center (PI: R.C.P., P50 AG016574) and Mayo Clinic Study on Aging (PI: R.C.P., U01 AG006786), as well as the neuropathology core in Rochester, MN (Dr. Joseph Parisi), without whose contributions this study would not have been possible.

Conflict of interest

R.C.P. has been chair of a safety monitoring committee for Pfizer (Wyeth) and Janssen Alzheimer Immunotherapy (Elan); and a consultant for Elan Pharmaceuticals and GE Healthcare. All other authors declare that they have no conflicts of interest.

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  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Mitsuru Shinohara, Dennis W. Dickson & Guojun Bu

  2. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Ronald C. Petersen

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  1. Mitsuru Shinohara
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Shinohara, M., Petersen, R.C., Dickson, D.W. et al. Brain regional correlation of amyloid-β with synapses and apolipoprotein E in non-demented individuals: potential mechanisms underlying regional vulnerability to amyloid-β accumulation. Acta Neuropathol 125, 535–547 (2013). https://doi.org/10.1007/s00401-013-1086-9

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