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


ABSTRACT: Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-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? in Alzheimer's disease (AD). In wild type mice, we show that A?40 (fluorescently labeled A?40 or unlabeled A?40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, A?42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to A?40. Interestingly, pretreatment with A?40 in the CSF, but not A?42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-? deposits, glymphatic transport was reduced, due to the accumulation of toxic A? species, such as soluble oligomers. CSF-derived A?40 co-localizes with existing endogenous vascular and parenchymal amyloid-? plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal A? accumulation. Importantly, glymphatic failure preceded significant amyloid-? 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.

SUBMITTER: Peng W 

PROVIDER: S-EPMC4980916 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-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 Aβ in Alzheimer's disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted  ...[more]

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