Dataset Information

Peripheral versus central nervous system APOE in Alzheimer's disease: Interplay across the blood-brain barrier.

ABSTRACT: The apolipoprotein E (APOE) ?4 allele has been demonstrated as the preeminent genetic risk factor for late onset Alzheimer's disease (AD), which comprises greater than 90% of all AD cases. The discovery of the connection between different APOE genotypes and AD risk in the early 1990s spurred three decades of intense and comprehensive research into the function of APOE in the normal and diseased brain. The importance of APOE in the periphery has been well established, due to its pivotal role in maintaining cholesterol homeostasis and cardiovascular health. The influence of vascular factors on brain function and AD risk has been extensively studied in recent years. As a major apolipoprotein regulating multiple molecular pathways beyond its canonical lipid-related functions in the periphery and the central nervous system, APOE represents a critical link between the two compartments, and may influence AD risk from both sides of the blood-brain barrier. This review discusses recent advances in understanding the different functions of APOE in the periphery and in the brain, and highlights several promising APOE-targeted therapeutic strategies for AD.

SUBMITTER: Chernick D

PROVIDER: S-EPMC6693948 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Peripheral versus central nervous system APOE in Alzheimer's disease: Interplay across the blood-brain barrier.

Chernick Dustin D Ortiz-Valle Stephanie S Jeong Angela A Qu Wenhui W Li Ling L

Neuroscience letters 20190607

The apolipoprotein E (APOE) ε4 allele has been demonstrated as the preeminent genetic risk factor for late onset Alzheimer's disease (AD), which comprises greater than 90% of all AD cases. The discovery of the connection between different APOE genotypes and AD risk in the early 1990s spurred three decades of intense and comprehensive research into the function of APOE in the normal and diseased brain. The importance of APOE in the periphery has been well established, due to its pivotal role in m ...[more]

PMID: 31181302

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Project description:In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.

Dataset Information

Peripheral versus central nervous system APOE in Alzheimer's disease: Interplay across the blood-brain barrier.

Publications

Peripheral versus central nervous system APOE in Alzheimer's disease: Interplay across the blood-brain barrier.

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