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.
Division of Clinical Neurosciences, Southampton General Hospital, University of Southampton, South Lab and Pathology Block, LD66 (Mailpoint 806), Tremona Road, Southampton, Hampshire, SO166YD, UK.
Cheryl A
CA
Hawkes
Wolfgang
W
Härtig
Johannes
J
Kacza
Reinhard
R
Schliebs
Roy O
RO
Weller
James A
JA
Nicoll
Roxana O
RO
Carare
D000367:Age Factors; D000375:Aging / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000098:blood supply* / Q000473:pathology*; D016657:Cerebral Amyloid Angiopathy / Q000150:complications* / Q000473:pathology*; D024141:Collagen Type IV / Q000378:metabolism; D003911:Dextrans; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D024141:Collagen Type IV; D003911:Dextrans; D005353:Fibronectins; D019812:Heparan Sulfate Proteoglycans; D007797:Laminin; C015219:fluorescein isothiocyanate dextran; C071927:perlecan; D016650:Fluorescein-5-isothiocyanate