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      Neurovascular dysfunction in vascular dementia, Alzheimer’s and atherosclerosis

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          Abstract

          Efficient blood supply to the brain is of paramount importance to its normal functioning and improper blood flow can result in potentially devastating neurological consequences. Cerebral blood flow in response to neural activity is intrinsically regulated by a complex interplay between various cell types within the brain in a relationship termed neurovascular coupling. The breakdown of neurovascular coupling is evident across a wide variety of both neurological and psychiatric disorders including Alzheimer’s disease. Atherosclerosis is a chronic syndrome affecting the integrity and function of major blood vessels including those that supply the brain, and it is therefore hypothesised that atherosclerosis impairs cerebral blood flow and neurovascular coupling leading to cerebrovascular dysfunction. This review will discuss the mechanisms of neurovascular coupling in health and disease and how atherosclerosis can potentially cause cerebrovascular dysfunction that may lead to cognitive decline as well as stroke. Understanding the mechanisms of neurovascular coupling in health and disease may enable us to develop potential therapies to prevent the breakdown of neurovascular coupling in the treatment of vascular brain diseases including vascular dementia, Alzheimer’s disease and stroke.

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          Most cited references50

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          Central nervous system pericytes in health and disease.

          Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier (BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.
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            Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

            Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
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              Expanded dynamic range of fluorescent indicators for Ca(2+) by circularly permuted yellow fluorescent proteins.

              Fluorescence resonance energy transfer (FRET) technology has been used to develop genetically encoded fluorescent indicators for various cellular functions. Although most indicators have cyan- and yellow-emitting fluorescent proteins (CFP and YFP) as FRET donor and acceptor, their poor dynamic range often prevents detection of subtle but significant signals. Here, we optimized the relative orientation of the two chromophores in the Ca(2+) indicator, yellow cameleon (YC), by fusing YFP at different angles. We generated circularly permuted YFPs (cpYFPs) that showed efficient maturation and acid stability. One of the cpYFPs incorporated in YC absorbs a great amount of excited energy from CFP in its Ca(2+)-saturated form, thereby increasing the Ca(2+)-dependent change in the ratio of YFP/CFP by nearly 600%. Both in cultured cells and in the nervous system of transgenic mice, the new YC enables visualization of subcellular Ca(2+) dynamics with better spatial and temporal resolution than before. Our study provides an important guide for the development and improvement of indicators using GFP-based FRET.
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                Author and article information

                Contributors
                oshabir1@sheffield.ac.uk
                j.berwick@sheffield.ac.uk
                s.francis@sheffield.ac.uk
                Journal
                BMC Neurosci
                BMC Neurosci
                BMC Neuroscience
                BioMed Central (London )
                1471-2202
                17 October 2018
                17 October 2018
                2018
                : 19
                : 62
                Affiliations
                [1 ]ISNI 0000 0004 1936 9262, GRID grid.11835.3e, The Neurovascular and Neuroimaging Research Group, Alfred Denny Building, , The University of Sheffield, ; Western Bank, Sheffield, S10 2TN UK
                [2 ]ISNI 0000 0004 1936 9262, GRID grid.11835.3e, Department of Infection, Immunity and Cardiovascular Disease, , The University of Sheffield, Medical School, ; Beech Hill Road, Sheffield, S10 2RX UK
                Author information
                http://orcid.org/0000-0001-7412-6966
                Article
                465
                10.1186/s12868-018-0465-5
                6192291
                30333009
                6be1bfbe-e41c-461e-bc7c-54ba36d3b70e
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 3 August 2018
                : 10 October 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MR/M013553/1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002283, Alzheimer’s Research UK;
                Award ID: ARUK-IRG2014
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Neurosciences
                neurovascular coupling,atherosclerosis,dementia,mouse,neuroimaging,disease modelling,alzheimer’s,vascular dementia

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