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.

Ischemic brain injury in cerebral amyloid angiopathy

“…17,18 More recent models have suggested that A in CAA is predominantly generated by neurons [19][20][21] and subsequently deposited in the vessel wall because of impairment in A clearance. Impaired A clearance may be caused by alterations in perivascular drainage pathways [22][23][24] and deficits in endothelial-mediated active transport of A into the blood. 25 Factors such as age-related arterial stiffening may contribute to the failure of perivascular drainage of A .…”

“…Thromboses, atherosclerosis, or arterial stiffening may abolish the motive force necessary for drainage of A through interstitial fluid pathways, which in turn enhances the accumulation of amyloid in the vessel wall. 23,24,57,91 The hypothesis that common age-related vascular diseases, such as atherosclerosis and arterial stiffening, trigger vascular amyloid deposition could also explain the rapid increase in the prevalence of CAA with aging. 3 An imaging marker of impaired clearance of interstitial fluid is dilated perivascular spaces.…”

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

“…Extracellular matrix (ECM) properties in the vessel wall are important for this perivascular filter by forming and maintaining basement membranes. The basement membranes are important for regulating cell growth, differentiation, and migration and consist of laminins, nidogens, collagen, and heparan sulfate proteoglycans (HSPGs) (Hawkes et al, 2011). HSPGs co-localize with the vascular deposits in AD and HCHWA-D (Van Horssen et al, 2001).…”

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

“…Age-related changes in levels of laminin, fibronectin, and perlecan have been reported in mouse brain capillaries (Hawkes et al, 2011). Vacuolization, reduplication, and thickening of capillary basement membranes have also been shown to occur in the human aged and AD brain (Perlmutter, 1994;Shimizu et al, 2009).…”