In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS

Wildsmith, Kristin R.; Basak, Jacob M.; Patterson, Bruce W.; Pyatkivskyy, Yuriy; Kim, Jung-Su; Yarasheski, Kevin E.; Wang, Jennifer X.; Mawuenyega, Kwasi G.; Jiang, Hong; Parsadanian, Maia; Yoon, Hyuk; Kasten, Tom; Sigurdson, Wendy; Xiong, Chengjie; Goate, Alison M.; Holtzman, David M.; Bateman, Randall J.

doi:10.1371/journal.pone.0038013

Cited by 48 publications

(52 citation statements)

References 51 publications

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“…The glymphatic fluid transport of CSF-derived apoE may also prevent dilution and wash out of astrocyte-secreted apoE, and facilitate a wider distribution of apoE within the parenchyma. In addition, glymphatic re-circulation of apoE may contribute to its slow turnover rate [90], and retention within brain [6]. …”

Section: Discussionmentioning

confidence: 99%

Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Achariyar

Peng

et al. 2016

Mol Neurodegeneration

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BackgroundApolipoprotein E (apoE) is a major carrier of cholesterol and essential for synaptic plasticity. In brain, it’s expressed by many cells but highly expressed by the choroid plexus and the predominant apolipoprotein in cerebrospinal fluid (CSF). The role of apoE in the CSF is unclear. Recently, the glymphatic system was described as a clearance system whereby CSF and ISF (interstitial fluid) is exchanged via the peri-arterial space and convective flow of ISF clearance is mediated by aquaporin 4 (AQP4), a water channel. We reasoned that this system also serves to distribute essential molecules in CSF into brain. The aim was to establish whether apoE in CSF, secreted by the choroid plexus, is distributed into brain, and whether this distribution pattern was altered by sleep deprivation.MethodsWe used fluorescently labeled lipidated apoE isoforms, lenti-apoE3 delivered to the choroid plexus, immunohistochemistry to map apoE brain distribution, immunolabeled cells and proteins in brain, Western blot analysis and ELISA to determine apoE levels and radiolabeled molecules to quantify CSF inflow into brain and brain clearance in mice. Data were statistically analyzed using ANOVA or Student’s t- test.ResultsWe show that the glymphatic fluid transporting system contributes to the delivery of choroid plexus/CSF-derived human apoE to neurons. CSF-delivered human apoE entered brain via the perivascular space of penetrating arteries and flows radially around arteries, but not veins, in an isoform specific manner (apoE2 > apoE3 > apoE4). Flow of apoE around arteries was facilitated by AQP4, a characteristic feature of the glymphatic system. ApoE3, delivered by lentivirus to the choroid plexus and ependymal layer but not to the parenchymal cells, was present in the CSF, penetrating arteries and neurons. The inflow of CSF, which contains apoE, into brain and its clearance from the interstitium were severely suppressed by sleep deprivation compared to the sleep state.ConclusionsThus, choroid plexus/CSF provides an additional source of apoE and the glymphatic fluid transporting system delivers it to brain via the periarterial space. By implication, failure in this essential physiological role of the glymphatic fluid flow and ISF clearance may also contribute to apoE isoform-specific disorders in the long term.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0138-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Achariyar

Peng

et al. 2016

Mol Neurodegeneration

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203

137

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“…Although an association between lower plasma ApoE level and increased risk of Alzheimer's disease was observed in this study, it is unclear whether there is any mechanistic link between them. Because peripheral ApoE cannot penetrate the blood-brain barrier (BBB) [9], there is no or very low correlation between plasma and CSF ApoE levels [10,11]. In another study, higher CSF ApoE levels were associated with higher CSF tau levels and cognitive decline in human [12].…”

Section: Regulation Of Apolipoprotein E Lipidation and Metabolismmentioning

confidence: 99%

Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

Liao

Yoon

Kim

2017

Current Opinion in Lipidology

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Purpose of reviewAPOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease.Recent findingsApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis.SummaryEmerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.

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“…It has also been established that apoE plays an important role in the homeostasis of A␤ in the brain, through its influence on both the deposition and the clearance of the peptide (9 -13). Emerging in vivo techniques in humans and other animal models further strengthen our understanding of the distributions of and relationships between A␤ and apoE in the brain (14,15). However, the interaction of A␤ with apoE is still poorly understood, with conflicting evidence with respect to differences in isoform interaction with A␤ (11).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Binding of Apolipoprotein E Inhibits the Oligomer Growth of Amyloid-β Peptide in Solution as Determined by Fluorescence Cross-correlation Spectroscopy

Altman

Petrlová

et al. 2013

Journal of Biological Chemistry

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Background: ApoE is the most significant risk factor for Alzheimer disease, with known effects on A␤ deposition in the brain. Results: ApoE binds to aggregating A␤ peptides and maintains a faster diffusion rate for the A␤ peptide over time. Conclusion: Binding of apoE to A␤ slows the oligomerization of A␤. Significance: FCCS measurements quantify isoform-dependent differences in apoE binding to A␤ in solution.

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In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS

Cited by 48 publications

References 51 publications

Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

Binding of Apolipoprotein E Inhibits the Oligomer Growth of Amyloid-β Peptide in Solution as Determined by Fluorescence Cross-correlation Spectroscopy

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