Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy

Abstract

The deposition of amyloid-β (Aβ) peptides in the walls of leptomeningeal and cortical blood vessels as cerebral amyloid angiopathy (CAA) is present in normal ageing and the majority of Alzheimer’s disease (AD) brains. The failure of clearance mechanisms to eliminate Aβ from the brain contributes to the development of sporadic CAA and AD. Here, we investigated the effects of CAA and ageing on the pattern of perivascular drainage of solutes in the brains of naïve mice and in the Tg2576 mouse model of AD. We report that drainage of small molecular weight dextran along cerebrovascular basement membranes is impaired in the hippocampal capillaries and arteries of 22-month-old wild-type mice compared to 3- and 7-month-old animals, which was associated with age-dependent changes in capillary density. Age-related alterations in the levels of laminin, fibronectin and perlecan in vascular basement membranes were also noted in wild-type mice. Furthermore, dextran was observed in the walls of veins of Tg2576 mice in the presence of CAA, suggesting that deposition of Aβ in vessel walls disrupts the normal route of elimination of solutes from the brain parenchyma. These data support the hypothesis that perivascular solute drainage from the brain is altered both in the ageing brain and as a consequence of CAA. These findings have implications for the success of therapeutic strategies for the treatment of AD that rely upon the health of the ageing cerebral vasculature.

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References

  1. 1.

    Ailles L, Kisilevsky R, Young ID (1993) Induction of perlecan gene expression precedes amyloid formation during experimental murine AA amyloidogenesis. Lab Investig 69:443–448

    PubMed  CAS  Google Scholar 

  2. 2.

    Akima M, Nonaka H, Kagesawa M, Tanaka K (1986) A study on the microvasculature of the cerebral cortex. Fundamental architecture and its senile change in the frontal cortex. Lab Investig 55:482–489

    PubMed  CAS  Google Scholar 

  3. 3.

    Aumailley M, Krieg T (1996) Laminins: a family of diverse multifunctional molecules of basement membranes. J Investig Dermatol 106:209–214

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118:103–113

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM et al (2008) Consequence of Aβ immunization on the vasculature of human Alzheimer’s disease brain. Brain 131:3299–3310

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Bradbury MW, Cserr HF, Westrop RJ (1981) Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol 240:F329–F336

    PubMed  CAS  Google Scholar 

  7. 7.

    Bronfman FC, Alvarez A, Morgan C, Inestrosa NC (1998) Laminin blocks the assembly of wild-type Aβ and the Dutch variant peptide into Alzheimer’s fibrils. Amyloid 5:16–23

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Bronfman FC, Garrido J, Alvarez A, Morgan C, Inestrosa NC (1996) Laminin inhibits amyloid-beta-peptide fibrillation. Neurosci Lett 218:201–203

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Burger S, Noack M, Kirazov LP, Kirazov EP, Naydenov CL, Kouznetsova E et al (2009) Vascular endothelial growth factor (VEGF) affects processing of amyloid precursor protein and beta-amyloidogenesis in brain slice cultures derived from transgenic Tg2576 mouse brain. Int J Dev Neurosci 27:517–523

    PubMed  Article  Google Scholar 

  10. 10.

    Burns EM, Kruckeberg TW, Gaetano PK (1981) Changes with age in cerebral capillary morphology. Neurobiol Aging 2:283–291

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH et al (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 96:14088–14093

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH et al (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

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Castillo GM, Ngo C, Cummings J, Wight TN, Snow AD (1997) Perlecan binds to the beta-amyloid proteins (Aβ) of Alzheimer’s disease, accelerates Aβ fibril formation, and maintains Aβ fibril stability. J Neurochem 69:2452–2465

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Christie R, Yamada M, Moskowitz M, Hyman B (2001) Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am J Pathol 158:1065–1071

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Chung YA, O JH, Kim JY, Kim KJ, Ahn KJ (2009) Hypoperfusion and ischemia in cerebral amyloid angiopathy documented by 99mTc-ECD brain perfusion SPECT. J Nucl Med 50:1969–1974

    PubMed  Article  Google Scholar 

  16. 16.

    Costell M, Gustafsson E, Aszodi A, Morgelin M, Bloch W, Hunziker E et al (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147:1109–1122

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Cotman SL, Halfter W, Cole GJ (2000) Agrin binds to beta-amyloid (Aβ), accelerates Aβ fibril formation, and is localized to Aβ deposits in Alzheimer’s disease brain. Mol Cell Neurosci 15:183–198

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Couchman JR, Abrahamson DR, McCarthy KJ (1993) Basement membrane proteoglycans and development. Kidney Int 43:79–84

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Deane R, Zlokovic BV (2007) Role of the blood–brain barrier in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 4:191–197

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Domnitz SB, Robbins EM, Hoang AW, Garcia-Alloza M, Hyman BT, Rebeck GW et al (2005) Progression of cerebral amyloid angiopathy in transgenic mouse models of Alzheimer disease. J Neuropathol Exp Neurol 64:588–594

    PubMed  CAS  Google Scholar 

  21. 21.

    Erickson AC, Couchman JR (2000) Still more complexity in mammalian basement membranes. J Histochem Cytochem 48:1291–1306

    PubMed  CAS  Google Scholar 

  22. 22.

    Haglund M, Kalaria R, Slade JY, Englund E (2006) Differential deposition of amyloid beta peptides in cerebral amyloid angiopathy associated with Alzheimer’s disease and vascular dementia. Acta Neuropathol 111:430–435

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Han BH, Zhou ML, Abousaleh F, Brendza RP, Dietrich HH, Koenigsknecht-Talboo J et al (2008) Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition. J Neurosci 28:13542–13550

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Hicks P, Rolsten C, Brizzee D, Samorajski T (1983) Age-related changes in rat brain capillaries. Neurobiol Aging 4:69–75

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Hooijmans CR, Graven C, Dederen PJ, Tanila H, van Groen T, Kiliaan AJ (2007) Amyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice. Brain Res 1181:93–103

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Hutchins PM, Lynch CD, Cooney PT, Curseen KA (1996) The microcirculation in experimental hypertension and aging. Cardiovasc Res 32:772–780

    PubMed  CAS  Google Scholar 

  27. 27.

    Ichimura T, Fraser PA, Cserr HF (1991) Distribution of extracellular tracers in perivascular spaces of the rat brain. Brain Res 545:103–113

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Jellinger KA, Lauda F, Attems J (2007) Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage. Eur J Neurol 14:923–928

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Kalaria RN (1996) Cerebral vessels in ageing and Alzheimer’s disease. Pharmacol Ther 72:193–214

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 21:372–381

    PubMed  CAS  Google Scholar 

  31. 31.

    Kiuchi Y, Isobe Y, Fukushima K (2002) Type IV collagen prevents amyloid beta-protein fibril formation. Life Sci 70:1555–1564

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Kiuchi Y, Isobe Y, Fukushima K, Kimura M (2002) Disassembly of amyloid beta-protein fibril by basement membrane components. Life Sci 70:2421–2431

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Knox SM, Whitelock JM (2006) Perlecan: how does one molecule do so many things? Cell Mol Life Sci 63:2435–2445

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Kouznetsova E, Klingner M, Sorger D, Sabri O, Grossmann U, Steinbach J et al (2006) Developmental and amyloid plaque-related changes in cerebral cortical capillaries in transgenic Tg2576 Alzheimer mice. Int J Dev Neurosci 24:187–193

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Krause DL, Muller N (2010) Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. Int J Alzheimers Dis

  36. 36.

    Martin AJ, Friston KJ, Colebatch JG, Frackowiak RS (1991) Decreases in regional cerebral blood flow with normal aging. J Cereb Blood Flow Metab 11:684–689

    PubMed  CAS  Google Scholar 

  37. 37.

    Massaad CA, Amin SK, Hu L, Mei Y, Klann E, Pautler RG (2010) Mitochondrial superoxide contributes to blood flow and axonal transport deficits in the Tg2576 mouse model of Alzheimer’s disease. PLoS One 5:e10561

    PubMed  Article  Google Scholar 

  38. 38.

    Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC et al (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330(6012):1774

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Miao J, Xu F, Davis J, Otte-Holler I, Verbeek MM, Van Nostrand WE (2005) Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol 167:505–515

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Miners JS, Ashby E, Van Helmond Z, Chalmers KA, Palmer LE, Love S et al (2008) Angiotensin-converting enzyme (ACE) levels and activity in Alzheimer’s disease, and relationship of perivascular ACE-1 to cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 34:181–193

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S (2008) Aβ-degrading enzymes in Alzheimer’s disease. Brain Pathol 18:240–252

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Moody DM, Brown WR, Challa VR, Ghazi-Birry HS, Reboussin DM (1997) Cerebral microvascular alterations in aging, leukoaraiosis, and Alzheimer’s disease. Ann NY Acad Sci 826:103–116

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Morgan C, Bugueno MP, Garrido J, Inestrosa NC (2002) Laminin affects polymerization, depolymerization and neurotoxicity of Aβ peptide. Peptides 23:1229–1240

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Natte R, Maat-Schieman ML, Haan J, Bornebroek M, Roos RA, van Duinen SG (2001) Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann Neurol 50:765–772

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Ochi H, Abraham M, Ishikawa H, Frenkel D, Yang K, Basso AS et al (2006) Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25− LAP + T cells. Nat Med 12:627–635

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Paris D, Patel N, DelleDonne A, Quadros A, Smeed R, Mullan M (2004) Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis. Neurosci Lett 366:80–85

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S et al (2005) NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci 25:1769–1777

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Patton RL, Kalback WM, Esh CL, Kokjohn TA, Van Vickle GD, Luehrs DC et al (2006) Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer’s disease patients: a biochemical analysis. Am J Pathol 169:1048–1063

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Perlmutter LS (1994) Microvascular pathology and vascular basement membrane components in Alzheimer’s disease. Mol Neurobiol 9:33–40

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ (2002) Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology 58:1629–1634

    PubMed  CAS  Google Scholar 

  51. 51.

    Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M et al (2002) Cerebral hemorrhage after passive anti-Aβ immunotherapy. Science 298:1379

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO (2003) Capillary and arterial cerebral 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

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Riddle DR, Sonntag WE, Lichtenwalner RJ (2003) Microvascular plasticity in aging. Ageing Res Rev 2:149–168

    PubMed  Article  Google Scholar 

  54. 54.

    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 Theor Biol 238:962–974

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Shimizu H, Ghazizadeh M, Sato S, Oguro T, Kawanami O (2009) Interaction between beta-amyloid protein and heparan sulfate proteoglycans from the cerebral capillary basement membrane in Alzheimer’s disease. J Clin Neurosci 16:277–282

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Shin HK, Jones PB, Garcia-Alloza M, Borrelli L, Greenberg SM, Bacskai BJ et al (2007) Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy. Brain 130:2310–2319

    PubMed  Article  Google Scholar 

  57. 57.

    Steffensen B, Chen Z, Pal S, Mikhailova M, Su J, Wang Y et al (2010) Fragmentation of fibronectin by inherent autolytic and matrix metalloproteinase activities. Matrix Biol

  58. 58.

    Szentistvanyi I, Patlak CS, Ellis RA, Cserr HF (1984) Drainage of interstitial fluid from different regions of rat brain. Am J Physiol 246:F835–F844

    PubMed  CAS  Google Scholar 

  59. 59.

    Tchougounova E, Forsberg E, Angelborg G, Kjellen L, Pejler G (2001) Altered processing of fibronectin in mice lacking heparin: a role for heparin-dependent mast cell chymase in fibronectin degradation. J Biol Chem 276:3772–3777

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Thal DR, Larionov S, Abramowski D, Wiederhold KH, Van Dooren T, Yamaguchi H et al (2007) Occurrence and co-localization of amyloid beta-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice. Neurobiol Aging 28:1221–1230

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Tian J, Shi J, Smallman R, Iwatsubo T, Mann DM (2006) Relationships in Alzheimer’s disease between the extent of Aβ deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen. Neuropathol Appl Neurobiol 32:332–340

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Timpl R (1996) Macromolecular organization of basement membranes. Curr Opin Cell Biol 8:618–624

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Topple A, Fifkova E, Cullen-Dockstader K (1990) Effect of age on blood vessels and neurovascular appositions in the rat dentate fascia. Neurobiol Aging 11:371–380

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Uspenskaia O, Liebetrau M, Herms J, Danek A, Hamann GF (2004) Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels. BMC Neurosci 5:37

    PubMed  Article  Google Scholar 

  65. 65.

    Van Dorpe J, Smeijers L, Dewachter I, Nuyens D, Spittaels K, Van Den Haute C et al (2000) Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons. Am J Pathol 157:1283–1298

    PubMed  Article  Google Scholar 

  66. 66.

    van Horssen J, Kleinnijenhuis J, Maass CN, Rensink AA, Otte-Holler I, David G et al (2002) Accumulation of heparan sulfate proteoglycans in cerebellar senile plaques. Neurobiol Aging 23:537–545

    PubMed  Article  Google Scholar 

  67. 67.

    van Horssen J, Otte-Holler I, David G, Maat-Schieman ML, van den Heuvel LP, Wesseling P et al (2001) Heparan sulfate proteoglycan expression in cerebrovascular amyloid beta deposits in Alzheimer’s disease and hereditary cerebral hemorrhage with amyloidosis (Dutch) brains. Acta Neuropathol 102:604–614

    PubMed  Google Scholar 

  68. 68.

    Weller RO, Boche D, Nicoll JA (2009) Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy. Acta Neuropathol 118:87–102

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Weller RO, Cohen NR, Nicoll JA (2004) Cerebrovascular disease and the pathophysiology of Alzheimer’s disease. Implications for therapy. Panminerva Med 46:239–251

    PubMed  CAS  Google Scholar 

  70. 70.

    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

    PubMed  Article  CAS  Google Scholar 

  71. 71.

    Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN et al (2004) Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation 1:24

    PubMed  Article  Google Scholar 

  72. 72.

    Wyss-Coray T, Lin C, Sanan DA, Mucke L, Masliah E (2000) Chronic overproduction of transforming growth factor-beta1 by astrocytes promotes Alzheimer’s disease-like microvascular degeneration in transgenic mice. Am J Pathol 156:139–150

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This work is funded by the Alzheimer’s Research Trust UK (C.A.H, J.N, R.O.C) and the German Alzheimer Forschung Initiative (R.S.). The authors would like to thank the Biomedical Imaging Unit (Southampton General Hospital), as well as Ute Bauer and Dr. Anke Hoffmann for excellent technical assistance. We would also like to express our gratitude to Dr. Karen Hsiao Ashe, Department of Neurology, University of Minnesota, USA, for kindly providing Tg2576 founder mice.

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The authors declare they have no conflict of interest.

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Correspondence to Roxana O. Carare.

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Hawkes, C.A., Härtig, W., Kacza, J. et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol 121, 431–443 (2011). https://doi.org/10.1007/s00401-011-0801-7

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Keywords

  • Alzheimer’s disease
  • Amyloid-β
  • Cerebral vasculature
  • Perivascular drainage
  • Basement membranes
  • Cerebral amyloid angiopathy