Advertisement

Acta Neuropathologica

, 118:87 | Cite as

Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy

  • Roy O. Weller
  • Delphine Boche
  • James A. R. Nicoll
Review

Abstract

The introduction of immunotherapy and its ultimate success will require re-evaluation of the pathogenesis of Alzheimer’s disease particularly with regard to the role of the ageing microvasculature and the effects of APOE genotype. Arteries in the brain have two major functions (a) delivery of blood and (b) elimination of interstitial fluid and solutes, including amyloid-β (Aβ), along perivascular pathways (lymphatic drainage). Both these functions fail with age and particularly severely in Alzheimer’s disease and vascular dementia. Accumulation of Aβ as plaques in brain parenchyma and artery walls as cerebral amyloid angiopathy (CAA) is associated with failure of perivascular elimination of Aβ from the brain in the elderly and in Alzheimer’s disease. High levels of soluble Aβ in the brain correlate with cognitive decline in Alzheimer’s disease and reflect the failure of perivascular drainage of solutes from the brain and loss of homeostasis of the neuronal environment. Clinically and pathologically, there is a spectrum of disease related to functional failure of the ageing microvasculature with “pure” Alzheimer’s disease at one end of the spectrum and vascular dementia at the other end. Changes in the cerebral microvasculature with age have a potential impact on therapy with cholinesterase inhibitors and especially on immunotherapy that removes Aβ from plaques in the brain, but results in an increase in severity of CAA and no clear improvement in cognition. Drainage of Aβ along perivascular pathways in ageing artery walls may need to be improved to maximise the potential for improvement of cognitive function with immunotherapy.

Keywords

Structure and functions of normal cerebral arteries Perivascular drainage of Aβ Cerebral amyloid angiopathy Microvascular disease Arteriosclerosis Arteriolosclerosis Vascular dementia Alzheimer’s disease Brain homeostasis Cholinesterase inhibitors Immunotherapy 

Notes

Acknowledgments

We thank Dr. Anton Page of the Biomedical Imaging Unit Southampton University Hospitals for preparing the figures for this paper. This study was supported by the Medical Research Council and the Alzheimer Research Trust. Research Ethics Committee Approval reference 07/H0505/86.

References

  1. 1.
    Abbott NJ (2004) Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:545–552. doi: 10.1016/j.neuint.2003.11.006 PubMedCrossRefGoogle Scholar
  2. 2.
    Alcolado R, Weller RO, Parrish EP, Garrod D (1988) The cranial arachnoid and pia mater in man: anatomical and ultrastructural observations. Neuropathol Appl Neurobiol 14:1–17. doi: 10.1111/j.1365-2990.1988.tb00862.x PubMedCrossRefGoogle Scholar
  3. 3.
    Attems J, Jellinger K (2004) Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol 107:83–90. doi: 10.1007/s00401-003-0796-9 PubMedCrossRefGoogle Scholar
  4. 4.
    Attems J, Lintner F, Jellinger KA (2004) Amyloid beta peptide 1-42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology. Acta Neuropathol 107:283–291. doi: 10.1007/s00401-004-0822-6 PubMedCrossRefGoogle Scholar
  5. 5.
    Attems J, Quass M, Jellinger KA, Lintner F (2007) Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology. J Neurol Sci 257:49–55. doi: 10.1016/j.jns.2007.01.013 PubMedCrossRefGoogle Scholar
  6. 6.
    Ballard CG, Chalmers KA, Todd C, McKeith IG, O’Brien JT, Wilcock G, Love S, Perry EK (2007) Cholinesterase inhibitors reduce cortical Abeta in dementia with Lewy bodies. Neurology 68:1726–1729. doi: 10.1212/01.wnl.0000261920.03297.64 PubMedCrossRefGoogle Scholar
  7. 7.
    Beach TG (2008) Physiologic origins of age-related beta-amyloid deposition. Neurodegener Dis 5:143–145. doi: 10.1159/000113685 PubMedCrossRefGoogle Scholar
  8. 8.
    Beach TG, Kuo YM, Spiegel K, Emmerling MR, Sue LI, Kokjohn K, Roher AE (2000) The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease. J Neuropathol Exp Neurol 59:308–313PubMedGoogle Scholar
  9. 9.
    Beach TG, Potter PE, Kuo YM, Emmerling MR, Durham RA, Webster SD, Walker DG, Sue LI, Scott S, Layne KJ, Roher AE (2000) Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition. Neurosci Lett 283:9–12. doi: 10.1016/S0304-3940(00)00916-2 PubMedCrossRefGoogle Scholar
  10. 10.
    Bechmann I, Galea I, Perry VH (2007) What is the blood–brain barrier (not)? Trends Immunol 28:5–11. doi: 10.1016/j.it.2006.11.007 PubMedCrossRefGoogle Scholar
  11. 11.
    Bedford L, Hay D, Paine S, Rezvani N, Mee M, Lowe J, Mayer RJ (2008) Is malfunction of the ubiquitin proteasome system the primary cause of alpha-synucleinopathies and other chronic human neurodegenerative disease? Biochim Biophys Acta 1782:683–690PubMedGoogle Scholar
  12. 12.
    Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, Zlokovic BV (2007) Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 27:909–918PubMedGoogle Scholar
  13. 13.
    Bergsneider M (2001) Evolving concepts of cerebrospinal fluid. Neurosurg Clin N Am 36:631–638Google Scholar
  14. 14.
    Black S, Gao F, Bilbao J (2008) Understanding white matter disease. Imaging–pathological correlations in vascular cognitive impairment. Stroke [Epub ahead of print]Google Scholar
  15. 15.
    Boche D, Nicoll JA (2008) The role of the immune system in clearance of Abeta from the brain. Brain Pathol 18:267–278. doi: 10.1111/j.1750-3639.2008.00134.x PubMedCrossRefGoogle Scholar
  16. 16.
    Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C, Nicoll JA (2008) Consequence of Abeta immunization on the vasculature of human Alzheimer’s disease brain. Brain 131:3299–3310. doi: 10.1093/brain/awn261 PubMedCrossRefGoogle Scholar
  17. 17.
    Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JAR, Perry VH, Weller RO (2008) Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries. Significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol 34:131–144. doi: 10.1111/j.1365-2990.2007.00926.x PubMedCrossRefGoogle Scholar
  18. 18.
    NGoM CFAS (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 357:169–175. doi: 10.1016/S0140-6736(00)03589-3 CrossRefGoogle Scholar
  19. 19.
    Chalmers K, Wilcock G, Love S (2005) Contributors to white matter damage in the frontal lobe in Alzheimer’s disease. Neuropathol Appl Neurobiol 31:623–631. doi: 10.1111/j.1365-2990.2005.00678.x PubMedCrossRefGoogle Scholar
  20. 20.
    Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM (2005) P-glycoprotein deficiency at the blood–brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest 115:3285–3290. doi: 10.1172/JCI25247 PubMedCrossRefGoogle Scholar
  21. 21.
    Cserr HF, Knopf PM (1992) Cervical lymphatics, the blood–brain barrier and the immunoreactivity of the brain: a new view. Immunol Today 13:507–512. doi: 10.1016/0167-5699(92)90027-5 PubMedCrossRefGoogle Scholar
  22. 22.
    Deane R, Zlokovic BV (2007) Role of the blood–brain barrier in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 4:191–197. doi: 10.2174/156720507780362245 PubMedCrossRefGoogle Scholar
  23. 23.
    Domnitz SB, Robbins EM, Hoang AW, Garcia-Alloza M, Hyman BT, Rebeck GW, Greenberg SM, Bacskai BJ, Frosch MP (2005) Progression of cerebral amyloid angiopathy in transgenic mouse models of Alzheimer disease. J Neuropathol Exp Neurol 64:588–594PubMedGoogle Scholar
  24. 24.
    Duvernoy HM, Delon S, Vannson JL (1981) Cortical blood vessels of the human brain. Brain Res Bull 7:519–579. doi: 10.1016/0361-9230(81)90007-1 PubMedCrossRefGoogle Scholar
  25. 25.
    Engelhardt B (2008) Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines. J Neurol Sci 274:23–26. doi: 10.1016/j.jns.2008.05.019 PubMedCrossRefGoogle Scholar
  26. 26.
    Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD (1999) Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet 354:919–920. doi: 10.1016/S0140-6736(99)02355-7 PubMedCrossRefGoogle Scholar
  27. 27.
    Farkas E, De Jong GI, de Vos RA, Jansen Steur EN, Luiten PG (2000) Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease. Acta Neuropathol 100:395–402. doi: 10.1007/s004010000195 PubMedCrossRefGoogle Scholar
  28. 28.
    Farkas E, de Vos RA, Donka G, Jansen Steur EN, Mihály A, Luiten PG (2006) Age-related microvascular degeneration in the human cerebral periventricular white matter. Acta Neuropathol 111:150–157. doi: 10.1007/s00401-005-0007-y PubMedCrossRefGoogle Scholar
  29. 29.
    Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, Kalaria RN, Forster G, Esteves F, Wharton SB, Shaw PJ, O’Brien JT, Ince PG (2006) White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke 37:1391–1398. doi: 10.1161/01.STR.0000221308.94473.14 PubMedCrossRefGoogle Scholar
  30. 30.
    Ferrer I, Boada Rovira M, Sánchez Guerra ML, Rey MJ, Costa-Jussá F (2004) Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 14:11–20PubMedGoogle Scholar
  31. 31.
    Ferrer I, Kaste M, Kalimo H Vascular diseases. In: Love S, Louis DN, Ellison DW, editors. Greenfield’s Neuropathology. Eighth ed. London: Hodder Arnold; 2008. p. 121–240.Google Scholar
  32. 32.
    Fisher A (2008) Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer’s disease. Neurotherapeutics 5:433–442. doi: 10.1016/j.nurt.2008.05.002 PubMedCrossRefGoogle Scholar
  33. 33.
    Glenner GG, Wong CW, Quaranta V, Eanes ED (1984) The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis. Appl Pathol 2:357–369PubMedGoogle Scholar
  34. 34.
    Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I (2006) T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol 80:797–801. doi: 10.1189/jlb.0306176 PubMedCrossRefGoogle Scholar
  35. 35.
    Hatterer E, Davoust N, Didier-Bazes M, Vuaillat C, Malcus C, Belin MF, Nataf S (2006) How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 107:806–812. doi: 10.1182/blood-2005-01-0154 PubMedCrossRefGoogle Scholar
  36. 36.
    Herzig MC, Van Nostrand WE, Jucker M (2006) Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models. Brain Pathol 16:40–54. doi: 10.1111/j.1750-3639.2006.tb00560.x PubMedCrossRefGoogle Scholar
  37. 37.
    Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223. doi: 10.1016/S0140-6736(08)61075-2 PubMedCrossRefGoogle Scholar
  38. 38.
    Hutchings M, Weller RO (1986) Anatomical relationships of the pia mater to cerebral blood vessels in man. J Neurosurg 65:316–325PubMedCrossRefGoogle Scholar
  39. 39.
    Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko S, Bi W, Paljug WR, Debnath ML, Hope CE, Isanski BA, Hamilton RL, DeKosky ST (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 131:1630–1645. doi: 10.1093/brain/awn016 PubMedCrossRefGoogle Scholar
  40. 40.
    Jellinger KA (2008) The pathology of “vascular dementia”: a critical update. J Alzheimers Dis 14:107–123PubMedGoogle Scholar
  41. 41.
    Jellinger KA, Attems J (2007) Neuropathological evaluation of mixed dementia. J Neurol Sci 257:80–87. doi: 10.1016/j.jns.2007.01.045 PubMedCrossRefGoogle Scholar
  42. 42.
    Kuo YM, Crawford F, Mullan M, Kokjohn TA, Emmerling MR, Weller RO, Roher AE (2000) Elevated A beta and apolipoprotein E in A betaPP transgenic mice and its relationship to amyloid accumulation in Alzheimer’s disease. Mol Med 6:430–439PubMedGoogle Scholar
  43. 43.
    Kuo YM, Emmerling MR, Vigo Pelfrey C, Kasunic TC, Kirkpatrick JB, Murdoch GH, Ball MJ, Roher AE (1996) Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem 271:4077–4081. doi: 10.1074/jbc.271.8.4077 PubMedCrossRefGoogle Scholar
  44. 44.
    Lahiri DK, Rogers JT, Greig NH, Sambamurti K (2004) Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents. Curr Pharm Des 10:3111–3119. doi: 10.2174/1381612043383331 PubMedCrossRefGoogle Scholar
  45. 45.
    Lashley T, Revesz T, Plant G, Bandopadhyay R, Lees AJ, Frangione B, Wood NW, de Silva R, Ghiso J, Rostagno A, Holton JL (2008) Expression of BRI2 mRNA and protein in normal human brain and familial British dementia: its relevance to the pathogenesis of disease. Neuropathol Appl Neurobiol 34:492–505. doi: 10.1111/j.1365-2990.2008.00935.x PubMedCrossRefGoogle Scholar
  46. 46.
    Layfield R, Lowe J, Bedford L (2005) The ubiquitin–proteasome system and neurodegenerative disorders. Essays Biochem 41:157–171. doi: 10.1042/EB0410157 PubMedCrossRefGoogle Scholar
  47. 47.
    Lossinsky AS, Shivers RR (2004) Structural pathways for macromolecular and cellular transport across the blood–brain barrier during inflammatory conditions. Histol Histopathol 19:535–564PubMedGoogle Scholar
  48. 48.
    Lowe J, Mirra SS, Hyman BT, Dickson DW et al (2008) Ageing and dementia. In: Love S, Louis DN, Ellison DW (eds) Greenfield’s neuropathology, 8th edn. Hodder Arnold, London, pp 1031–1152Google Scholar
  49. 49.
    Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155:853–862PubMedGoogle Scholar
  50. 50.
    Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, Seubert P, Games D, Kirby L, Schenk D (2005) Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64:129–131PubMedGoogle Scholar
  51. 51.
    McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866. doi:10.1002/1531-8249(199912)46:6<860::AID-ANA8>3.0.CO;2-MPubMedCrossRefGoogle Scholar
  52. 52.
    Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S (2008) Abeta-degrading enzymes in Alzheimer’s disease. Brain Pathol 18:240–252. doi: 10.1111/j.1750-3639.2008.00132.x PubMedCrossRefGoogle Scholar
  53. 53.
    Miners JS, Van Helmond Z, Chalmers K, Wilcock G, Love S, Kehoe PG (2006) Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J Neuropathol Exp Neurol 65:1012–1021PubMedCrossRefGoogle Scholar
  54. 54.
    Moody DM, Brown WR, Challa VR, Ghazi-Birry HS, Reboussin DM (1997) Cerebral microvascular alterations in aging, leukoaraiosis, and Alzheimer’s disease. Ann N Y Acad Sci 826:103–116. doi: 10.1111/j.1749-6632.1997.tb48464.x PubMedCrossRefGoogle Scholar
  55. 55.
    Nagasawa S, Handa H, Okumura A, Naruo Y, Moritake K, Hayashi K (1979) Mechanical properties of human cerebral arteries. Part 1: Effects of age and vascular smooth muscle activation. Surg Neurol 12:297–304PubMedGoogle Scholar
  56. 56.
    Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C (2006) Abeta species removal after Abeta42 immunization. J Neuropathol Exp Neurol 65:1040–1048. doi: 10.1097/01.jnen.0000240466.10758.ce PubMedCrossRefGoogle Scholar
  57. 57.
    Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452. doi: 10.1038/nm840 PubMedCrossRefGoogle Scholar
  58. 58.
    Nicoll JAR, Yamada M, Frackowiak J, Mazur Kolecka B, Weller RO (2004) Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease. Pro-CAA position statement. Neurobiol Aging 25:589–597. doi: 10.1016/j.neurobiolaging.2004.02.003 Discussion 603-604PubMedCrossRefGoogle Scholar
  59. 59.
    Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C (2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61:46–54PubMedGoogle Scholar
  60. 60.
    Oshima K, Akiyama H, Tsuchiya K, Kondo H, Haga C, Shimomura Y, Iseki E, Uchikado H, Kato M, Niizato K, Arai H (2006) Relative paucity of tau accumulation in the small areas with abundant Abeta42-positive capillary amyloid angiopathy within a given cortical region in the brain of patients with Alzheimer pathology. Acta Neuropathol 111:510–518. doi: 10.1007/s00401-006-0070-z PubMedCrossRefGoogle Scholar
  61. 61.
    Owens T, I. B, Engelhardt B (2008) Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol 67:1113–1121. doi: 10.1097/NEN.0b013e31818f9ca8
  62. 62.
    Patton RL, Kalback WM, Esh CL, Kokjohn TA, Van Vickle GD, Luehrs DC, Kuo YM, Lopez J, Brune D, Ferrer I, Masliah E, Newel AJ, Beach TG, Castano EM, Roher AE (2006) Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer’s disease patients: a biochemical analysis. Am J Pathol 169:1048–1063. doi: 10.2353/ajpath.2006.060269 PubMedCrossRefGoogle Scholar
  63. 63.
    Perry EK, Kilford L, Lees AJ, Burn DJ, Perry RH (2003) Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs. Ann Neurol 54:235–238. doi: 10.1002/ana.10639 PubMedCrossRefGoogle Scholar
  64. 64.
    Poirier J, Derouesne C (1985) Le concept de lacune cerebrale de 1838 a nos jours. Rev Neurol 141:3–17PubMedGoogle Scholar
  65. 65.
    Pollock H, Hutchings M, Weller RO, Zhang ET (1997) Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes. J Anat 191:337–346. doi: 10.1046/j.1469-7580.1997.19130337.x PubMedCrossRefGoogle Scholar
  66. 66.
    Preston SD, Steart PV, Wilkinson A, Nicoll JAR, Weller RO (2003) Capillary and arterial amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29:106–117. doi: 10.1046/j.1365-2990.2003.00424.x PubMedCrossRefGoogle Scholar
  67. 67.
    Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL (2003) Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol 62:885–898PubMedGoogle Scholar
  68. 68.
    Roher AE, Kuo Y-M, Esh C, Knebel C, Weiss N, Kalback W, Luehrs DC, Childress JL, Beach TG, Weller RO, Kokjohn TA (2003) Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol Med 9:112–122PubMedGoogle Scholar
  69. 69.
    Roher AE, Lowenson JD, Clarke S, Wolkow C, Wang R, Cotter RJ, Reardon IM, Zurcher Neely HA, Heinrikson RL, Ball MJ et al (1993) Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer’s disease. J Biol Chem 268:3072–3083PubMedGoogle Scholar
  70. 70.
    Salzman KL, Osborn AG, House P, Jinkins JR, Ditchfield A, Cooper JA, Weller RO (2005) Giant tumefactive perivascular spaces. AJNR Am J Neuroradiol 26:298–305PubMedGoogle Scholar
  71. 71.
    Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177. doi: 10.1038/22124 PubMedCrossRefGoogle Scholar
  72. 72.
    Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO (2006) Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theory Biol 238:962–974. doi: 10.1016/j.jtbi.2005.07.005 CrossRefGoogle Scholar
  73. 73.
    Scholz W (1938) Studien zur Pathologie der Hirngefässe II. Die drusige Entartung der Hirnarterien und -capillaren (Eine Form seniler Gefässerkrankung). Zeitschrift für die gesamte. Neurol Psychiatr (Bucur) 162:694–715Google Scholar
  74. 74.
    Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D (2008) Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci 28:6787–6793. doi: 10.1523/JNEUROSCI.2377-07.2008 PubMedCrossRefGoogle Scholar
  75. 75.
    Scolding NJ, Joseph F, Kirby PA, Mazanti I, Gray F, Mikol J, Ellison D, Hilton DA, Williams TL, MacKenzie JM, Xuereb JH, Love S (2005) Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 128:500–515. doi: 10.1093/brain/awh379 PubMedCrossRefGoogle Scholar
  76. 76.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766PubMedGoogle Scholar
  77. 77.
    Selkoe DJ (2006) Amyloid beta-peptide is produced by cultured cells during normal metabolism: a reprise. J Alzheimers Dis 9:163–168PubMedGoogle Scholar
  78. 78.
    Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer’s amyloid-beta(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 PubMedCrossRefGoogle Scholar
  79. 79.
    Shinkai Y, Yoshimura M, Ito Y, Odaka A, Suzuki N, Yanagisawa K, Ihara Y (1995) Amyloid beta -proteins 1-40 and 1-42(43) in the soluble fraction of extra- and intracranial blood vessels. Ann Neurol 38:421–428. doi: 10.1002/ana.410380312 PubMedCrossRefGoogle Scholar
  80. 80.
    Szentistvanyi I, Patlak CS, Ellis RA, Cserr HF (1984) Drainage of interstitial fluid from different regions of rat brain. Am J Physiol 246:F835–F844PubMedGoogle Scholar
  81. 81.
    Thal DR, Ghebremedhin E, Orantes M, Wiestler OD (2003) Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287–1301PubMedGoogle Scholar
  82. 82.
    Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Tredici KD, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293PubMedGoogle Scholar
  83. 83.
    Tian J, Shi J, Bailey K, Mann DM (2003) Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer’s disease. Neurosci Lett 352:137–140. doi: 10.1016/j.neulet.2003.08.048 PubMedCrossRefGoogle Scholar
  84. 84.
    Tian J, Shi J, Bailey K, Mann DM (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. doi: 10.1046/j.0305-1846.2003.00510.x PubMedCrossRefGoogle Scholar
  85. 85.
    Tsubuki S, Takaki Y, Saido TC (2003) Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. Lancet 361:1957–1958. doi: 10.1016/S0140-6736(03)13555-6 PubMedCrossRefGoogle Scholar
  86. 86.
    Vinters HV, Wang ZZ, Secor DL (1996) Brain parenchymal and microvascular amyloid in Alzheimer’s disease. Brain Pathol 6:179–195. doi: 10.1111/j.1750-3639.1996.tb00799.x PubMedCrossRefGoogle Scholar
  87. 87.
    Walsh DM, Selkoe DJ (2007) Abeta oligomers—a decade of discovery. J Neurochem 101:1172–1184. doi: 10.1111/j.1471-4159.2006.04426.x PubMedCrossRefGoogle Scholar
  88. 88.
    Weller RO (1998) Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. J Neuropathol Exp Neurol 57:885–894. doi: 10.1097/00005072-199810000-00001 PubMedCrossRefGoogle Scholar
  89. 89.
    Weller RO (2005) Microscopic morphology and histology of the human meninges. Morphologie 89:22–34. doi: 10.1016/S1286-0115(05)83235-7 PubMedCrossRefGoogle Scholar
  90. 90.
    Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117:1–14. doi: 10.1007/s00401-008-0457-0 PubMedCrossRefGoogle Scholar
  91. 91.
    Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE (1998) Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol 153:725–733PubMedGoogle Scholar
  92. 92.
    Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266. doi: 10.1111/j.1750-3639.2008.00133.x PubMedCrossRefGoogle Scholar
  93. 93.
    Weller RO, Yow HY, Preston SD, Mazanti I, Nicoll JAR (2002) Cerebrovascular disease is a major factor in the failure of elimination of Abeta from the aging human brain: implications for therapy of Alzheimer’s disease. Ann N Y Acad Sci 977:162–168PubMedCrossRefGoogle Scholar
  94. 94.
    Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D (2004) Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflamm 1:24. doi: 10.1186/1742-2094-1-24 CrossRefGoogle Scholar
  95. 95.
    Wisniewski HM, Wegiel J (1994) Beta-amyloid formation by myocytes of leptomeningeal vessels. Acta Neuropathol 87:233–241. doi: 10.1007/BF00296738 PubMedCrossRefGoogle Scholar
  96. 96.
    Yow HY, Weller RO (2002) A role for cerebrovascular disease in determining the pattern of beta amyloid deposition in Alzheimer’s disease. Neuropathol Appl Neurobiol 28:149. doi: 10.1046/j.1365-2990.2002.39286_4.x CrossRefGoogle Scholar
  97. 97.
    Zhang-Nunes SX, Maat-Schieman ML, van Duinen SG, Roos RA, Frosch MP, Greenberg SM (2006) The cerebral beta-amyloid angiopathies: hereditary and sporadic. Brain Pathol 16:30–39. doi: 10.1111/j.1750-3639.2006.tb00559.x PubMedCrossRefGoogle Scholar
  98. 98.
    Zhang ET, Inman CB, Weller RO (1990) Interrelationships of the pia mater and the perivascular (Virchow–Robin) spaces in the human cerebrum. J Anat 170:111–123PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Roy O. Weller
    • 1
  • Delphine Boche
    • 1
  • James A. R. Nicoll
    • 1
  1. 1.Clinical Neurosciences, University of Southampton School of Medicine, LD74, South Laboratory & Pathology BlockSouthampton General HospitalSouthamptonUK

Personalised recommendations