Impairment of paravascular clearance pathways in the aging brain

作者：Benjamin T. Kress, Jeffrey J. Iliff, Maosheng Xia, Minghuan Wang, Helen Wei, Douglas Zeppenfeld, Lulu Xie, Hongyi Kang, Qiwu Xu, Jason Liew, Benjamin A. Plog, Fengfei Ding, Rashid Deane, Maiken Nedergaard · 发表于：Annals of Neurology · 年份：2014 · DOI：10.1002/ana.24271 · 被引用次数：1540 · 研究领域：Cerebrospinal fluid and hydrocephalus、Traumatic Brain Injury and Neurovascular Disturbances、Intracerebral and Subarachnoid Hemorrhage Research

OBJECTIVE: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. METHODS: CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. RESULTS: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. INTE...