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Focal demyelination in Alzheimer’s disease and transgenic mouse models

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Abstract

We have investigated alterations in myelin associated with Aβ plaques, a major pathological hallmark of Alzheimer’s disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Aβ pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Aβ plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Aβ plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation.

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References

  1. Albert M, Antel J, Brück W, Stadelmann C (2007) Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol 17:129–138

    Article  PubMed  Google Scholar 

  2. Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J (2003) White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study. Arch Neurol 60:393–398

    Article  PubMed  Google Scholar 

  3. Bartzokis G (2004) Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging 25:5–18 author reply 49–62

    Article  CAS  PubMed  Google Scholar 

  4. Bauer J, Bradl M, Klein M, Leisser M, Deckwerth TL, Wekerle H et al (2002) Endoplasmic reticulum stress in PLP-overexpressing transgenic rats: gray matter oligodendrocytes are more vulnerable than white matter oligodendrocytes. J Neuropathol Exp Neurol 61:12–22

    PubMed  Google Scholar 

  5. Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA et al (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945

    Article  CAS  PubMed  Google Scholar 

  6. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10(Suppl):S2–S9

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Braak H, Del Tredici K, Schultz C, Braak E (2000) Vulnerability of select neuronal types to Alzheimer’s disease. Ann NY Acad Sci 924:53–61

    CAS  PubMed  Google Scholar 

  9. Brady ST, Witt AS, Kirkpatrick LL, de Waegh SM, Readhead C, Tu PH et al (1999) Formation of compact myelin is required for maturation of the axonal cytoskeleton. J Neurosci 19:7278–7288

    CAS  PubMed  Google Scholar 

  10. Brown WR, Moody DM, Thore CR, Challa VR (2000) Cerebrovascular pathology in Alzheimer’s disease and leukoaraiosis. Ann NY Acad Sci 903:39–45

    Article  CAS  PubMed  Google Scholar 

  11. Brun A, Englund E (1986) A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 19:253–262

    Article  CAS  PubMed  Google Scholar 

  12. Burns JM, Church JA, Johnson DK, Xiong C, Marcus D, Fotenos AF et al (2005) White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease. Arch Neurol 62:1870–1876

    Article  PubMed  Google Scholar 

  13. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C et al (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 

  14. Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H (2008) Multiple sclerosis and Alzheimer’s disease. Ann Neurol 63:174–183

    Article  PubMed  Google Scholar 

  15. de la Monte SM (1989) Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer’s disease. Ann Neurol 25:450–459

    Article  Google Scholar 

  16. Desai MK, Sudol KL, Janelsins MC, Mastrangelo MA, Frazer ME, Bowers WJ (2009) Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia 57:54–65

    Article  PubMed  Google Scholar 

  17. DeWitt DA, Silver J (1996) Regenerative failure: a potential mechanism for neuritic dystrophy in Alzheimer’s disease. Exp Neurol 142:103–110

    Article  CAS  PubMed  Google Scholar 

  18. Dickson TC, King CE, McCormack GH, Vickers JC (1999) Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease. Exp Neurol 156:100–110

    Article  CAS  PubMed  Google Scholar 

  19. Dickson TC, Vickers JC (2001) The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer’s disease. Neuroscience 105:99–107

    Article  CAS  PubMed  Google Scholar 

  20. Fancy SP, Harrington EP, Huang JK, Zhao C, Rowitch DH, Franklin RM (2010) Overcoming remyelination failure in multiple sclerosis and other myelin disorders. Exp Neurol [Epub ahead of print]

  21. Haglund M, Englund E (2002) Cerebral amyloid angiopathy, white matter lesions and Alzheimer encephalopathy—a histopathological assessment. Dement Geriatr Cogn Disord 14:161–166

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Hardy J (2009) The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem 110:1129–1134

    Article  CAS  PubMed  Google Scholar 

  24. Hildebrand C, Remahl S, Persson H, Bjartmar C (1993) Myelinated nerve fibres in the CNS. Prog Neurobiol 40:319–384

    Article  CAS  PubMed  Google Scholar 

  25. Hoos MD, Ahmed M, Smith SO, Van Nostrand WE (2009) Myelin basic protein binds to and inhibits the fibrillar assembly of Aβ42 in vitro. Biochemistry 48:4720–4727

    Article  CAS  PubMed  Google Scholar 

  26. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S et al (1996) Correlative memory deficits, abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102

    Article  CAS  PubMed  Google Scholar 

  27. Ihara M, Polvikoski TM, Hall R, Slade JY, Perry RH, Oakley AE et al (2010) Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies. Acta Neuropathol. doi:10.1007/s00401-009-0635-8

  28. Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131:1464–1477

    Article  CAS  PubMed  Google Scholar 

  29. Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M 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

    Article  CAS  PubMed  Google Scholar 

  30. Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu H-Y, Hyman BT, Bacskai BJ (2008) Abeta 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 

  31. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712

    Article  PubMed  Google Scholar 

  32. Le R, Cruz L, Urbanc B, Knowles RB, Hsiao-Ashe K, Duff K et al (2001) Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption. J Neuropathol Exp Neurol 60:753–758

    CAS  PubMed  Google Scholar 

  33. Li S, Liu BP, Budel S, Li M, Ji B, Walus L et al (2004) Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury. J Neurosci 24:10511–10520

    Article  CAS  PubMed  Google Scholar 

  34. Liao M-C, Ahmed M, Smith SO, Van Nostrand WE (2009) Degradation of amyloid beta protein by purified myelin basic protein. J Biol Chem 284:28917–28925

    Article  CAS  PubMed  Google Scholar 

  35. Lindner M, Fokuhl J, Linsmeier F, Trebst C, Stangel M (2009) Chronic toxic demyelination in the central nervous system leads to axonal damage despite remyelination. Neurosci Lett 453:120–125

    Article  CAS  PubMed  Google Scholar 

  36. Matsuo A, Lee GC, Terai K, Takami K, Hickey WF, McGeer EG et al (1997) Unmasking of an unusual myelin basic protein epitope during the process of myelin degeneration in humans: a potential mechanism for the generation of autoantigens. Am J Pathol 150:1253–1266

    CAS  PubMed  Google Scholar 

  37. Meier-Ruge W, Ulrich J, Brühlmann M, Meier E (1992) Age-related white matter atrophy in the human brain. Ann NY Acad Sci 673:260–269

    Article  CAS  PubMed  Google Scholar 

  38. Merkler D, Ernsting T, Kerschensteiner M, Brück W, Stadelmann C (2006) A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain 129:1972–1983

    Article  PubMed  Google Scholar 

  39. Peters A, Verderosa A, Sethares C (2008) The neuroglial population in the primary visual cortex of the aging rhesus monkey. Glia 56:1151–1161

    Article  PubMed  Google Scholar 

  40. Phinney AL, Deller T, Stalder M, Calhoun ME, Frotscher M, Sommer B et al (1999) Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice. J Neurosci 19:8552–8559

    CAS  PubMed  Google Scholar 

  41. Pistorio AL, Hendry SH, Wang X (2006) A modified technique for high-resolution staining of myelin. J Neurosci Methods 15:135–146

    Article  CAS  Google Scholar 

  42. Power J, Mayer-Pröschel M, Smith J, Noble M (2002) Oligodendrocyte precursor cells from different brain regions express divergent properties consistent with the differing time courses of myelination in these regions. Dev Biol 245:362–375

    Article  CAS  PubMed  Google Scholar 

  43. Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 45:358–368

    Article  CAS  PubMed  Google Scholar 

  44. Reisberg B, Franssen EH, Hasan SM, Monteiro I, Boksay I, Souren LE et al (1999) Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer’s and other dementing processes. Eur Arch Psychiatry Clin Neurosci 249(Suppl 3):28–36

    PubMed  Google Scholar 

  45. Ringman JM, O’Neill J, Geschwind D, Medina L, Apostolova LG, Rodriguez Y et al (2007) Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer’s disease mutations. Brain 130:1767–1776

    Article  PubMed  Google Scholar 

  46. Roher AE, Weiss N, Kokjohn TA, Kuo YM, Kalback W, Anthony J et al (2002) Increased Aβ peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer’s disease†. Biochemistry 41:11080–11090

    Article  CAS  PubMed  Google Scholar 

  47. Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RM et al (2008) Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci 11:1024–1034

    Article  CAS  PubMed  Google Scholar 

  48. Sjöbeck M, Englund E (2006) White matter mapping in Alzheimer’s disease: a neuropathological study. Neurobiol Aging 27:673–680

    Article  PubMed  Google Scholar 

  49. Skaper SD, Evans NA, Soden PE, Rosin C, Facci L, Richardson JC (2009) Oligodendrocytes are a novel source of amyloid peptide generation. Neurochem Res 34:2243–2250

    Article  CAS  Google Scholar 

  50. Song YJC, Lundvig DS, Huang Y, Gai WP, Blumbergs PC, Højrup P et al (2007) p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 171:1291–1303

    Article  CAS  PubMed  Google Scholar 

  51. Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT et al (2005) Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 25:7278–7287

    Article  CAS  PubMed  Google Scholar 

  52. Stricker NH, Schweinsburg BC, Delano-Wood L, Wierenga CE, Bangen KJ, Haaland KY et al (2009) Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer’s disease supports retrogenesis. Neuroimage 45:10–16

    Article  CAS  PubMed  Google Scholar 

  53. Svennerholm L, Gottfries CG (1994) Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J Neurochem 62:1039–1047

    Article  CAS  PubMed  Google Scholar 

  54. Tang Y, Nyengaard JR, Pakkenberg B, Gundersen HJ (1997) Age-induced white matter changes in the human brain: a stereological investigation. Neurobiol Aging 18:609–615

    Article  CAS  PubMed  Google Scholar 

  55. Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293

    PubMed  Google Scholar 

  56. Tian J, Shi J, Bailey K, Mann DA (2004) Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer’s disease. Neuropathol Appl Neurobiol 30:46–56

    Article  CAS  PubMed  Google Scholar 

  57. Tomidokoro Y, Harigaya Y, Matsubara E, Ikeda M, Kawarabayashi T, Shirao T et al (2001) Brain Abeta amyloidosis in APPsw mice induces accumulation of presenilin-1 and tau. J Pathol 194:500–506

    Article  CAS  PubMed  Google Scholar 

  58. Tsai J, Grutzendler J, Duff K, Gan WB (2004) Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7:1181–1183

    Article  CAS  PubMed  Google Scholar 

  59. Vickers JC, Chin D, Edwards AM, Sampson V, Harper C, Morrison J (1996) Dystrophic neurite formation associated with age-related beta amyloid deposition in the neocortex: clues to the genesis of neurofibrillary pathology. Exp Neurol 141:1–11

    Article  CAS  PubMed  Google Scholar 

  60. Woodhouse A, Dickson TC, West AK, McLean CA, Vickers JC (2006) No difference in expression of apoptosis-related proteins and apoptotic morphology in control, pathologically aged and Alzheimer’s disease cases. Neurobiol Dis 22:323–333

    Article  CAS  PubMed  Google Scholar 

  61. Woodhouse A, Shepherd CE, Sokolova A, Carroll VL, King AE, Halliday GM et al (2009) Cytoskeletal alterations differentiate presenilin-1 and sporadic Alzheimer’s disease. Acta Neuropathol 117:19–29

    Article  CAS  PubMed  Google Scholar 

  62. Xu J, Chen S, Ahmed SH, Chen H, Ku G, Goldberg MP et al (2001) Amyloid-beta peptides are cytotoxic to oligodendrocytes. J Neurosci 21:RC118

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded by the Australian National Health and Medical Research Council and the J.O. and J.R. Wicking Trust (ANZ Charitable Services). The PS-1 human familial AD cases were provided by the Prince of Wales Medical Research Institute Tissue Resource Centre which is funded through an enabling grant from the Australian National Health and Medical Research Council. We thank Professor Poul H Jensen for providing the rabbit anti p25α antibody.

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The authors declare that they have no conflict of interest.

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Correspondence to Tracey C. Dickson.

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Mitew, S., Kirkcaldie, M.T.K., Halliday, G.M. et al. Focal demyelination in Alzheimer’s disease and transgenic mouse models. Acta Neuropathol 119, 567–577 (2010). https://doi.org/10.1007/s00401-010-0657-2

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