Deletion of the eIF2α Kinase GCN2 Fails to Rescue the Memory Decline Associated with Alzheimer’s Disease
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{"title"=>"Deletion of the eIF2α Kinase GCN2 Fails to Rescue the Memory Decline Associated with Alzheimer's Disease", "type"=>"journal", "authors"=>[{"first_name"=>"Latha", "last_name"=>"Devi", "scopus_author_id"=>"14419610600"}, {"first_name"=>"Masuo", "last_name"=>"Ohno", "scopus_author_id"=>"56134343500"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84885398154", "doi"=>"10.1371/journal.pone.0077335", "pui"=>"370004661", "pmid"=>"24146979", "scopus"=>"2-s2.0-84885398154", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"7e746d26-8643-332f-9b86-66700d6ee6aa", "abstract"=>"Emerging evidence suggests that dysregulated translation through phosphorylation of eukaryotic initiation factor-2α (eIF2α) may contribute to Alzheimer's disease (AD) and related memory impairments. However, the underlying mechanisms remain unclear. Here, we crossed knockout mice for an eIF2α kinase (GCN2: general control nonderepressible-2 kinase) with 5XFAD transgenic mice, and investigated whether GCN2 deletion affects AD-like traits in this model. As observed in AD brains, 5XFAD mice recapitulated significant elevations in the β-secretase enzyme BACE1 and the CREB repressor ATF4 concomitant with a dramatic increase of eIF2α phosphorylation. Contrary to expectation, we found that GCN2(-/-) and GCN2(+/-) deficiencies aggravate rather than suppress hippocampal BACE1 and ATF4 elevations in 5XFAD mice, failing to rescue memory deficits as tested by the contextual fear conditioning. The facilitation of these deleterious events resulted in exacerbated β-amyloid accumulation, plaque pathology and CREB dysfunction in 5XFAD mice with GCN2 mutations. Notably, GCN2 deletion caused overactivation of the PKR-endoplasmic reticulum-related kinase (PERK)-dependent eIF2α phosphorylation pathway in 5XFAD mice in the absence of changes in the PKR pathway. Moreover, PERK activation in response to GCN2 deficiency was specific to 5XFAD mice, since phosphorylated PERK levels were equivalent between GCN2(-/-) and wild-type control mice. Our findings suggest that GCN2 may be an important eIF2α kinase under the physiological condition, whereas blocking the GCN2 pathway under exposure to significant β-amyloidosis rather aggravates eIF2α phosphorylation leading to BACE1 and ATF4 elevations in AD.", "link"=>"http://www.mendeley.com/research/deletion-eif2%CE%B1-kinase-gcn2-fails-rescue-memory-decline-associated-alzheimers-disease", "reader_count"=>42, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>11, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>15, "Student > Master"=>4, "Other"=>1, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>11, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>15, "Student > Master"=>4, "Other"=>1, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>18, "Medicine and Dentistry"=>9, "Neuroscience"=>4, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>4}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>18}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "India"=>1, "Spain"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1234011"], "description"=>"<p>(A) Representative immunoblots of protein extracts from hippocampal homogenates of mice. (B) Immunoreactive bands were quantified and expressed as the percentage of 5XFAD control mice (<i>n</i> = 6–8). Note that GCN2<sup>−/−</sup> deletion further increases ATF4 expression and accordingly reduces levels of phosphorylated CREB without affecting total CREB in 5XFAD mice. *<i>p</i><0.05 vs. wild-type, <sup>#</sup><i>p</i><0.05 vs. 5XFAD. All data are presented as mean ± SEM.</p>", "links"=>[], "tags"=>["gcn2", "deletion", "atf4", "creb", "pathways", "5xfad"], "article_id"=>820788, "categories"=>["Biological Sciences"], "users"=>["Latha Devi", "Masuo Ohno"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0077335.g004", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_GCN2_deletion_on_ATF4_and_CREB_pathways_in_5XFAD_mice_/820788", "title"=>"Effects of GCN2 deletion on ATF4 and CREB pathways in 5XFAD mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-11 03:32:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1234008"], "description"=>"<p>(A, C, D) Representative immunoblots of protein extracts from hippocampal homogenates of mice. (B, E) Immunoreactive bands were quantified and expressed as the percentage of 5XFAD control mice (<i>n</i> = 5–12). Note that GCN2 deficiencies aggravate eIF2α phosphorylation without affecting total eIF2α levels in 5XFAD mice. Moreover, GCN2 deletion induces overactivation of another eIF2α kinase PERK in 5XFAD mice, while PKR activities are not changed. *<i>p</i><0.05 vs. wild-type, <sup>#</sup><i>p</i><0.05 vs. 5XFAD. All data are presented as mean ± SEM.</p>", "links"=>[], "tags"=>["gcn2", "deletion", "phosphorylation", "pathways", "5xfad"], "article_id"=>820785, "categories"=>["Biological Sciences"], "users"=>["Latha Devi", "Masuo Ohno"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0077335.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_GCN2_deletion_on_eIF2_945_phosphorylation_pathways_in_5XFAD_mice_/820785", "title"=>"Effects of GCN2 deletion on eIF2α phosphorylation pathways in 5XFAD mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-11 03:32:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1234000"], "description"=>"<p>(A) GCN2<sup>−/−</sup> and GCN2<sup>+/−</sup> deficiencies had no effects on memory impairments in 5XFAD mice (*<i>p</i><0.05 vs. wild-type), as tested by the contextual fear conditioning (<i>n</i> = 11–19). (B) Representative immunoblots of protein extracts from hippocampal homogenates of mice. (C) Immunoreactive bands were quantified and expressed as the percentage of 5XFAD control mice (<i>n</i> = 5–8). Note that GCN2 mutations further increase BACE1 and C99 levels without affecting APP overexpression in 5XFAD mice (*<i>p</i><0.05 vs. wild-type, <sup>#</sup><i>p</i><0.05 vs. 5XFAD). (D) Levels of total Aβ40 and Aβ42 were quantified by sandwich ELISAs of guanidine extracts of hippocampal samples and expressed as the percentage of 5XFAD controls (<i>n</i> = 5–10). GCN2 mutations also significantly elevate Aβ40 and Aβ42 concentrations in 5XFAD mice (<sup>#</sup><i>p</i><0.05 vs. 5XFAD). All data are presented as mean ± SEM.</p>", "links"=>[], "tags"=>["gcn2", "deletion", "deficits", "app", "5xfad"], "article_id"=>820778, "categories"=>["Biological Sciences"], "users"=>["Latha Devi", "Masuo Ohno"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0077335.g001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_GCN2_deletion_on_memory_deficits_and_946_amyloidogenic_processing_of_APP_in_5XFAD_mice_/820778", "title"=>"Effects of GCN2 deletion on memory deficits and β-amyloidogenic processing of APP in 5XFAD mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-11 03:32:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1234006"], "description"=>"<p>(A) Brain sections were immunostained with the 6E10 anti-Aβ antibody. Shown are representative photomicrographs of the hippocampal region. Scale bar = 500 µm. (B) Percentage area occupied by Aβ deposits in the hippocampus was measured for quantification (<i>n</i> = 6–8). GCN2<sup>−/−</sup> deletion exacerbates plaque burden in 5XFAD mice (<sup>#</sup><i>p</i><0.05 vs. 5XFAD). Data are presented as mean ± SEM. (C) Double immunofluorescence labeling with 6E10 anti-Aβ (green) and anti-BACE1 (red) antibodies (<i>n</i> = 3–4). Note the high degree of colocalization of Aβ and BACE1 immunoreactivities in the hippocampus of 5XFAD and GCN2<sup>−/−</sup>·5XFAD mice. Scale bar = 50 µm.</p>", "links"=>[], "tags"=>["gcn2", "deletion", "plaque-associated", "elevation", "bace1", "5xfad"], "article_id"=>820783, "categories"=>["Biological Sciences"], "users"=>["Latha Devi", "Masuo Ohno"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0077335.g002", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_GCN2_deletion_on_A_946_load_and_plaque_associated_elevation_of_BACE1_expression_in_5XFAD_mice_/820783", "title"=>"Effects of GCN2 deletion on Aβ load and plaque-associated elevation of BACE1 expression in 5XFAD mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-11 03:32:40"}

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Relative Metric

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