Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele
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{"title"=>"Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele", "type"=>"journal", "authors"=>[{"first_name"=>"Cheryl A.", "last_name"=>"Hawkes", "scopus_author_id"=>"12242641800"}, {"first_name"=>"Patrick M.", "last_name"=>"Sullivan", "scopus_author_id"=>"7402033460"}, {"first_name"=>"Sarah", "last_name"=>"Hands", "scopus_author_id"=>"23984764600"}, {"first_name"=>"Roy O.", "last_name"=>"Weller", "scopus_author_id"=>"7201400620"}, {"first_name"=>"James A.R.", "last_name"=>"Nicoll", "scopus_author_id"=>"7005562167"}, {"first_name"=>"Roxana O.", "last_name"=>"Carare", "scopus_author_id"=>"23767970500"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"365398520", "doi"=>"10.1371/journal.pone.0041636", "sgr"=>"84864691664", "scopus"=>"2-s2.0-84864691664", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"22848551"}, "id"=>"88c55d31-3d27-3242-976e-7da150780cca", "abstract"=>"Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Aβ(40). Aβ(40) aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.", "link"=>"http://www.mendeley.com/research/disruption-arterial-perivascular-drainage-amyloid%CE%B2-brains-mice-expressing-human-apoe-%CE%B54-allele", "reader_count"=>49, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>9, "Researcher"=>8, "Student > Ph. D. Student"=>11, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>10, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>9, "Researcher"=>8, "Student > Ph. D. Student"=>11, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>10, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>13, "Agricultural and Biological Sciences"=>23, "Neuroscience"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Physics and Astronomy"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>13}, "Neuroscience"=>{"Neuroscience"=>3}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>23}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"Canada"=>1, "Netherlands"=>1, "United States"=>2, "United Kingdom"=>1, "Italy"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/603004"], "description"=>"<p>Photomicrographs of a transverse section of a bifurcating leptomeningeal artery in a wildtype mouse (a–d), demonstrating the distribution of intracerebrally-injected Aβ (green, c and d) along laminin-positive (red, a and d) basement membranes in the tunica media (identified by the presence of α-smooth muscle actin, blue, b and d). Co-localization of laminin, α-smooth muscle actin and Aβ is observed as white or bright pink. In the TRE3 mice (e–h), Aβ (green, g and h) distributed along the entire length of laminin-positive (red, e and h) basement membranes of the tunica adventitia and in the tunica media of a hippocampal leptomeningeal artery (blue, f and h). In the TRE4 mice (i–l), most of the Aβ (green, k and l) was observed as large deposits (arrows) in the basement membrane (red, i and l) of hippocampal arteries (blue, j and l). Scale bars  = 25 µm.</p>", "links"=>[], "tags"=>["cerebrovasculature", "16-month", "tre3", "tre4"], "article_id"=>273480, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636.g002", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distribution_of_human_A_40_within_the_cerebrovasculature_of_16_month_old_wildtype_TRE3_and_TRE4_mice_/273480", "title"=>"Distribution of human Aβ<sub>40</sub> within the cerebrovasculature of 16-month old wildtype, TRE3 and TRE4 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-25 00:58:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/603764"], "description"=>"<p>Brain tissue sections from wildtype (a, d, g, j), TRE3 (b, e, h, k) and TRE4 mice (c, f, i, l) were processed by immunocytochemistry for laminin, collagen IV and perlecan. The staining intensity of laminin (a–c) and collagen IV (d–f) was significantly lower in the blood vessels of TRE4 mice and had a patchy appearance compared to wildtype and TRE3 mice. Perlecan levels remained unchanged across genotypes (g–i), as did the pattern of glut-l endothelial cell labeling (j–l). Scale bars: a–l = 100 µm; m–o = 200 µm.</p>", "links"=>[], "tags"=>["membrane", "levels", "morphology", "cortical", "capillaries", "16-month", "tre3", "tre4"], "article_id"=>274246, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636.g006", "stats"=>{"downloads"=>0, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cerebrovascular_basement_membrane_levels_and_morphology_in_cortical_capillaries_of_16_month_old_wildtype_TRE3_and_TRE4_mice_/274246", "title"=>"Cerebrovascular basement membrane levels and morphology in cortical capillaries of 16-month old wildtype, TRE3 and TRE4 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-25 01:10:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/603220"], "description"=>"<p>Double labeling immunocytochemistry was used to assess the location of Aβ (green) aggregates (arrows) with respect to laminin-positive basement membranes (blue) in hippocampal arteries and glut-1-positive endothelial cells (red, a–d), GFAP-positive astrocytes (red, e–h), Iba-1-positive juxtavascular microglia (red, i–l) and CD163-positive perivascular macrophages (red, m–p). No co-localization was observed between Aβ aggregates and any cell type, suggesting that the Aβ deposits do not represent intracellular aggregates. Inserts represent x63 magnification. Scale bar: a–1 = 50 µm; m–p = 25 µm.</p>", "links"=>[], "tags"=>["deposits", "vessels", "16-month", "tre4"], "article_id"=>273699, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636.g003", "stats"=>{"downloads"=>0, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Localization_of_the_A_946_deposits_in_the_blood_vessels_of_16_month_old_TRE4_mice_/273699", "title"=>"Localization of the Aβ deposits in the blood vessels of 16-month old TRE4 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-25 01:01:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/603400"], "description"=>"<p>Frontal-parietal brain homogenates in 3-month old (a–c) and 16-month-old (d–f) TRE3, TRE4 and wildtype controls were analyzed by Western blotting for the levels of laminin (a, d), collagen IV (b, e) and agrin (c, f). Levels of laminin and collagen IV were significantly higher in the brains of 3-month old, but not 16-month old TRE3 and TRE4 mice versus wildtype mice. Agrin levels were unchanged between wildtype, TRE3 and TRE4 mice at either age. Optic density ratios of protein to GAPDH levels from 3 blots per antibody were analyzed by repeated measures two-way ANOVA with Bonferroni post-hoc test. Histograms represent mean optic density ratio values ± S.E.M., *p<0.05, **p<0.01, ***p<0.001.</p>", "links"=>[], "tags"=>["membrane", "levels", "brains", "3-", "16-month", "tre3", "tre4"], "article_id"=>273873, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636.g004", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Basement_membrane_protein_levels_in_the_brains_of_3_and_16_month_old_wildtype_TRE3_and_TRE4_mice_/273873", "title"=>"Basement membrane protein levels in the brains of 3- and 16-month old wildtype, TRE3 and TRE4 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-25 01:04:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/603910"], "description"=>"*<p>p<0.05, TRE3 vs. TRE4.</p>", "links"=>[], "tags"=>["membrane", "levels", "tre3", "tre4", "mice"], "article_id"=>274385, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636.t002", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Percent_change_in_basement_membrane_levels_of_TRE3_and_TRE4_mice_with_age_/274385", "title"=>"Percent change in basement membrane levels of TRE3 and TRE4 mice with age.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-07-25 01:13:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/315472"], "description"=>"<div><p>Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (<em>APOE)</em> ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the <em>APOE</em> ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human <em>APOE3</em> (TRE3) or <em>APOE4</em> (TRE4) genes and wildtype mice received intracerebral injections of human Aβ<sub>40</sub>. Aβ<sub>40</sub> aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that <em>APOE4</em> may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.</p> </div>", "links"=>[], "tags"=>["disruption", "arterial", "perivascular", "drainage", "brains", "mice", "expressing", "apoe", "allele"], "article_id"=>122269, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Disruption_of_Arterial_Perivascular_Drainage_of_Amyloid_from_the_Brains_of_Mice_Expressing_the_Human_APOE_4_Allele/122269", "title"=>"Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-25 00:37:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/602776"], "description"=>"<p>Photomicrographs of a hippocampal leptomeningeal artery in a wildtype mouse (a–d), demonstrating the even distribution of intracerebrally-injected Aβ (green, c and d) along laminin-positive (red, a and d) basement membranes of the tunica adventitia and the tunica media (identified by the presence of α-smooth muscle actin, blue, b and d). Co-localization of laminin, α-smooth muscle actin and Aβ is observed as bright pink. In the TRE3 mice (e–h), Aβ (green, g and h) also distributed evenly along the entire length of laminin-positive (red, e and h) basement membranes in the tunica media of a hippocampal artery (blue, f and h). By contrast, in the TRE4 mice (i–l), Aβ (green, k and l) was uniformly distributed along the basement membrane of the glia limitans (red, i and l), but appeared aggregated (arrow) in the basement membrane within the tunica media of the hippocampal artery (blue, j and l). Scale bars: a–d = 10 µm; e–h = 25 µm; i–l = 25 µm.</p>", "links"=>[], "tags"=>["cerebral", "vasculature", "3-month", "tre3", "tre4"], "article_id"=>273258, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636.g001", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distribution_of_human_A_40_within_the_cerebral_vasculature_of_3_month_old_wildtype_TRE3_and_TRE4_mice_/273258", "title"=>"Distribution of human Aβ<sub>40</sub> within the cerebral vasculature of 3-month old wildtype, TRE3 and TRE4 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-25 00:54:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/603958"], "description"=>"*<p>p<0.05, TRE3 vs. TRE4.</p>", "links"=>[], "tags"=>["deposits", "hippocampi", "3-", "16-month", "tre3", "tre4"], "article_id"=>274437, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636.t001", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Number_of_A_946_deposits_in_the_hippocampi_of_3_and_16_month_old_TRE3_and_TRE4_mice_/274437", "title"=>"Number of Aβ deposits in the hippocampi of 3- and 16-month old TRE3 and TRE4 mice.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-07-25 01:13:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/603564"], "description"=>"<p>Brain tissue sections from wildtype (a, d, g, j), TRE3 (b, e, h, k) and TRE4 mice (c, f, i, l) were processed for laminin, collagen IV and perlecan immunocytochemistry. The staining intensity of both laminin (a–c) and collagen IV (d–f) was higher in TRE3 and TRE4 mice, compared to wildtype animals. Perlecan levels were constant across genotypes (g–i). No differences were noted in the pattern of glut-l labeling of endothelial cells between mouse groups (j–l). Scale bars: a–l = 100 µm; m–o = 200 µm.</p>", "links"=>[], "tags"=>["morphology", "cerebrovascular", "membrane", "proteins", "cortical", "capillaries", "3-month", "tre3", "tre4"], "article_id"=>274035, "categories"=>["Biochemistry", "Cell Biology", "Neuroscience"], "users"=>["Cheryl A. Hawkes", "Patrick M. Sullivan", "Sarah Hands", "Roy O. Weller", "James A. R. Nicoll", "Roxana O. Carare"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0041636.g005", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Levels_and_morphology_of_cerebrovascular_basement_membrane_proteins_in_cortical_capillaries_of_3_month_old_wildtype_TRE3_and_TRE4_mice_/274035", "title"=>"Levels and morphology of cerebrovascular basement membrane proteins in cortical capillaries of 3-month old wildtype, TRE3 and TRE4 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-25 01:07:15"}

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Relative Metric

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