Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy
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.
KeywordsAlzheimer’s disease Amyloid-β Cerebral vasculature Perivascular drainage Basement membranes Cerebral amyloid angiopathy
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.
Conflict of interest
The authors declare they have no conflict of interest.
- 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 27:517–523PubMedCrossRefGoogle Scholar
- 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 34:131–144PubMedCrossRefGoogle Scholar
- 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 28:13542–13550PubMedCrossRefGoogle Scholar
- 35.Krause DL, Muller N (2010) Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. Int J Alzheimers DisGoogle Scholar
- 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 167:505–515PubMedCrossRefGoogle Scholar
- 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 50:765–772PubMedCrossRefGoogle Scholar
- 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 BiolGoogle Scholar
- 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 32:332–340PubMedCrossRefGoogle Scholar
- 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 102:604–614PubMedGoogle Scholar
- 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 1:24PubMedCrossRefGoogle Scholar