Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease

Glymphatic transport, defined as cerebrospinal fluid (CSF) ped-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble A beta in Alzheimer's disease (AD). In wild type mice, we show that A beta 40 (fluorescently labeled A beta 40 or unlabeled A beta 40), was distributed from CSF to brain, via the ped-arterial space, and associated with neurons. In contrast, A beta 42 was mostly restricted to the ped-arterial space due mainly to its greater propensity to oligomerize when compared to A beta 40. Interestingly, pretreatment with A beta 40 in the CSF, but not A beta 42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-beta deposits, glymphatic transport was reduced, due to the accumulation of toxic AS species, such as soluble oligomers. CSF-derived A beta 40 co-localizes with existing endogenous vascular and parenchymal amyloid-beta plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal A beta accumulation. Importantly, glymphatic failure preceded significant amyloid-beta deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD. (C) 2016 Elsevier Inc. All rights reserved.