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      Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

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          Abstract

          Montagne et al. examine the role of blood–brain barrier (BBB) dysfunction in Alzheimer’s neurodegeneration and how targeting the BBB can influence the course of neurological disorder in transgenic models with human APP, PSEN1 and TAU mutations, APOE4 (major genetic risk), and pericyte degeneration causing loss of BBB integrity.

          Abstract

          The blood–brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer’s disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.

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          Most cited references114

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          Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.

          Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.
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            RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.

            Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.
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              Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.

              The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                06 November 2017
                : 214
                : 11
                : 3151-3169
                Affiliations
                [1 ]Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA
                [2 ]Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA
                Author notes
                Correspondence to Berislav V. Zlokovic:zlokovic@usc.edu
                [*]

                A. Montagne and Z. Zhao contributed equally to this paper.

                Author information
                http://orcid.org/0000-0002-6802-8232
                Article
                20171406
                10.1084/jem.20171406
                5679168
                29061693
                ab0b6ad4-435f-4ffd-8bde-a365c2c54578
                © 2017 Montagne et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 05 August 2017
                : 22 September 2017
                : 26 September 2017
                Funding
                Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;
                Award ID: R01AG023084
                Award ID: R01NS090904
                Award ID: R01NS034467
                Award ID: R01AG039452
                Award ID: 5P01AG052350
                Funded by: Cure for Alzheimer’s Fund, DOI http://dx.doi.org/10.13039/100007625;
                Funded by: Alzheimer’s Association, DOI http://dx.doi.org/10.13039/100000957;
                Funded by: Fondation Leducq, DOI http://dx.doi.org/10.13039/501100001674;
                Award ID: 16 CVD 05
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                Medicine
                Medicine

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