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Neurobiol Dis. 2016 Sep;93:215-25. doi: 10.1016/j.nbd.2016.05.015. Epub 2016 May 24.

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

Author information

1
Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
2
Department of Anesthesia, Stony Brook University, Stony Brook, NY, USA; Department of Radiology, Stony Brook University, Stony Brook, NY, USA.
3
Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: Rashid_Deane@urmc.rochester.edu.

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 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 to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β 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.

KEYWORDS:

AQP4; Alzheimer's disease; Amyloid-β; Astrocytes; Brain ISF clearance; CSF; Clearance; Convective ISF flow; Glymphatic pathways; Lymphatic system

PMID:
27234656
PMCID:
PMC4980916
DOI:
10.1016/j.nbd.2016.05.015
[Indexed for MEDLINE]
Free PMC Article

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