An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome
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{"title"=>"An anti-β-amyloid vaccine for treating cognitive deficits in a mouse model of Down syndrome", "type"=>"journal", "authors"=>[{"first_name"=>"Pavel V.", "last_name"=>"Belichenko", "scopus_author_id"=>"57198253952"}, {"first_name"=>"Rime", "last_name"=>"Madani", "scopus_author_id"=>"6603449067"}, {"first_name"=>"Lorianne", "last_name"=>"Rey-Bellet", "scopus_author_id"=>"57188669006"}, {"first_name"=>"Maria", "last_name"=>"Pihlgren", "scopus_author_id"=>"57188669238"}, {"first_name"=>"Ann", "last_name"=>"Becker", "scopus_author_id"=>"56857127500"}, {"first_name"=>"Adeline", "last_name"=>"Plassard", "scopus_author_id"=>"57188666449"}, {"first_name"=>"Stephanie", "last_name"=>"Vuillermot", "scopus_author_id"=>"25931798800"}, {"first_name"=>"Valérie", "last_name"=>"Giriens", "scopus_author_id"=>"18037161000"}, {"first_name"=>"Rachel L.", "last_name"=>"Nosheny", "scopus_author_id"=>"6506887698"}, {"first_name"=>"Alexander M.", "last_name"=>"Kleschevnikov", "scopus_author_id"=>"6602826261"}, {"first_name"=>"Janice S.", "last_name"=>"Valletta", "scopus_author_id"=>"6602984133"}, {"first_name"=>"Sara K.S.", "last_name"=>"Bengtsson", "scopus_author_id"=>"57188665223"}, {"first_name"=>"Gordon R.", "last_name"=>"Linke", "scopus_author_id"=>"57188672247"}, {"first_name"=>"Michael T.", "last_name"=>"Maloney", "scopus_author_id"=>"11242017400"}, {"first_name"=>"David T.", "last_name"=>"Hickman", "scopus_author_id"=>"7005183595"}, {"first_name"=>"Pedro", "last_name"=>"Reis", "scopus_author_id"=>"57196698093"}, {"first_name"=>"Anne", "last_name"=>"Granet", "scopus_author_id"=>"55874663800"}, {"first_name"=>"Dorin", "last_name"=>"Mlaki", "scopus_author_id"=>"57188663118"}, {"first_name"=>"Maria Pilar", "last_name"=>"Lope-Deber", "scopus_author_id"=>"57188661875"}, {"first_name"=>"Long", "last_name"=>"Do", "scopus_author_id"=>"57188672383"}, {"first_name"=>"Nishant", "last_name"=>"Singhal", "scopus_author_id"=>"19036349000"}, {"first_name"=>"Eliezer", "last_name"=>"Masliah", "scopus_author_id"=>"35377063800"}, {"first_name"=>"Matthew L.", "last_name"=>"Pearn", "scopus_author_id"=>"36705041300"}, {"first_name"=>"Andrea", "last_name"=>"Pfeifer", "scopus_author_id"=>"8273906800"}, {"first_name"=>"Andreas", "last_name"=>"Muhs", "scopus_author_id"=>"55606296300"}, {"first_name"=>"William C.", "last_name"=>"Mobley", "scopus_author_id"=>"7006497542"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "doi"=>"10.1371/journal.pone.0152471", "sgr"=>"84962159014", "scopus"=>"2-s2.0-84962159014", "isbn"=>"1932-6203", "pmid"=>"27023444", "pui"=>"609350941"}, "id"=>"8b50103d-c013-3cbe-b84b-40948007335e", "abstract"=>"In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer's disease (AD). At present, no treatment targets Aβ-related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1-15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS.", "link"=>"http://www.mendeley.com/research/anti%CE%B2amyloid-vaccine-treating-cognitive-deficits-mouse-model-down-syndrome-1", "reader_count"=>19, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Other"=>1, "Student > Bachelor"=>6, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Other"=>1, "Student > Bachelor"=>6, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>4, "Neuroscience"=>4, "Chemistry"=>3, "Psychology"=>2, "Immunology and Microbiology"=>1, "Unspecified"=>1}, "reader_count_by_subdiscipline"=>{"Neuroscience"=>{"Neuroscience"=>4}, "Chemistry"=>{"Chemistry"=>3}, "Psychology"=>{"Psychology"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United Kingdom"=>1, "France"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/4910071"], "description"=>"<p>(A) APP mRNA was significantly increased in the Ts65Dn brain relative to the 2N control (<i>p</i> = 0.006). The data are mean ± SD, n (pooled samples) = 6. (B) Full length APP, CTFs and Aβ40 were significantly increased in the Ts65Dn brain as compared to 2N controls (<i>p</i> = 0.00001, <i>p</i> = 0.002 and <i>p</i> = 0.002 respectively). The values are mean ± SEM: the number of samples (N for mice, n for pooled samples) was: full length APP: 2N, N = 5; Ts65Dn, N = 5. APP-CTF’s: 2N, N = 5; Ts65Dn, N = 5. Aβ 40: 2N, n = 3; Ts65Dn, n = 3. ***—<i>p</i> < 0.001, ****—<i>p</i> < 0.0001. Error bars, SEM. <i>p</i> values were calculated using two-tailed Student T test.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3151939, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/APP_expression_in_the_brain_of_postnatal_Ts65Dn_mice_/3151939", "title"=>"APP expression in the brain of postnatal Ts65Dn mice.", "pos_in_sequence"=>2, "defined_type"=>1, "published_date"=>"2016-03-29 07:56:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/4910179"], "description"=>"<p>(A) Confocal images of GFAP (left) and CD45 immunoreactivity (right) in vehicle- and DS-01 treated 2N and Ts65Dn mice. Arrows point individual CD45-positive microglial cells. Images are from cortex (Scale bars = 100μm). (B) Quantification of GFAP immunoreactive optical density revealed no difference between treatment groups in either layers II-II motor cortex (left) or superior blade of dentate gyrus (right). Error bars, SEM. The number of mice used was as follows: 2N- vehicle/Ts65Dn- vehicle/2N-DS-01/Ts65Dn-DS-01 = 4/4/4/4. (C and D) There was little if any effect of vaccination on the levels of IFN and TNF in the plasma and in brain extracts from 2N and Ts65Dn mice. IL-1 and IL-6 decreased following immunization in the plasma of Ts65Dn mice treated with the DS-01 vaccine (One-way ANOVA, Bonferroni's multiple comparison test **—<i>p</i> < 0.01 and *—<i>p</i> < 0.05 respectively). Error bars, SEM. The number of mice used was as follows: 2N-vehicle/Ts65Dn-vehicle/2N-DS-01/Ts65Dn-DS-01 = 7/10/8/12. (E) Staining of cortical sections with Perls Prussian blue, immunostaining with anti-CD4 antibody, and H&E revealed the absence of positive staining in all experimental groups. These results are evidence against lymphocytic infiltration or microhemorrhage in vaccinated mice. The number of mice used was as follows: 2N- vehicle/Ts65Dn- vehicle/2N-DS-01/Ts65Dn-DS-01 = 3/5/5/5.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3152041, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471.g008", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Measures_of_inflammatory_markers_following_immunization_with_either_vehicle_or_DS_01_/3152041", "title"=>"Measures of inflammatory markers following immunization with either vehicle or DS-01.", "pos_in_sequence"=>9, "defined_type"=>1, "published_date"=>"2016-03-29 07:56:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/4910149"], "description"=>"<p>(A) The difference in spontaneous locomotor activity between 2N and Ts65Dn mice was unaffected by immunization. (B) In comparison to mice treated with vehicle, both 2N and Ts65Dn immunized with DS-01 showed significantly enhanced discrimination index (DI) in the novel object recognition test (two-tailed Student T test, <i>p</i> = 0.03). The number of mice used was as follows: 2N- vehicle/Ts65Dn- vehicle/2N-DS-01/Ts65Dn-DS-01 = 18/11/20/13. (C) Positive correlation between the level of anti-Aβ40 IgG and the DI (Spearman r correlation 0.4, <i>p</i> = 0.002). Mice having no titers and spreading over the entire range of DI are those immunized with vehicle. The two top performing (highest DI%) are vehicle-treated 2N mice and the two worth performing (lowest DI%) are vehicle-treated Ts65Dn mice. Data from both 2N and Ts65Dn mice immunized with DS-01 are spread in a cloud (solid circle) above DI of 70% while the majority of vehicle-immunized mice had a lower DI value (dashed circle). (D) In the fear conditioning test, during the contextual session, vehicle-treated Ts65Dn mice showed significantly less freezing versus 2N vehicle-treated mice (two-tailed Student T test, <i>p</i> = 0.004). In vaccinated Ts65Dn mice, freezing was significantly different from vehicle-treated Ts65Dn (two-tailed Student T test <i>p</i> = 0.05) and not significantly different from that in 2N vaccinated mice (two-tailed Student T test <i>p</i> = 0.3). *—<i>p</i> < 0.05, **—<i>p</i> < 0.01; Error bars, SEM. The number of mice used was as follows: 2N- vehicle/Ts65Dn- vehicle/2N-DS-01/Ts65Dn-DS-01 = 18/11/20/12.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3152011, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Behavioral_evaluation_and_memory_function_following_DS_01_immunization_/3152011", "title"=>"Behavioral evaluation and memory function following DS-01 immunization.", "pos_in_sequence"=>7, "defined_type"=>1, "published_date"=>"2016-03-29 07:56:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/4910119"], "description"=>"<p>(A) The levels of Aβ42 and (B) Aβ40 in brain samples from 2N and Ts65Dn mice. With respect to 2N vehicle-treated mice, Ts65Dn vehicle-treated mice showed significantly higher levels of Aβ42 and Aβ40 (two-tailed Student T test <i>p</i> = 0.031 and <i>p</i> = 0.007 respectively). In Ts65Dn immunized mice, Aβ42 and Aβ40 levels were not significantly different to those in 2N immunized mice (two-tailed Student T test <i>p</i> = 0.21 and <i>p</i> = 0.22). The number of mice used was as follows: 2N-vehicle/Ts65Dn-vehicle/2N-DS-01/Ts65Dn-DS-01 = 18/11/19/13. (C and D) Ratio of regional levels of Aβ42 and Aβ40 in 2N and Ts65Dn immunized mice relative to their corresponding vehicle controls. For Ts65Dn mice, but not 2N mice, there was a trend to lower Aβ levels following vaccination. This was most evident for Aβ40. The number of mice used was as follows: 2N-DS-01/Ts65Dn-DS-01 = 10/8. (E) Aβ40 in the plasma was increased in Ts65Dn mice (One-way ANOVA, Bonferroni's multiple comparison test <i>p</i> < 0.05); following immunization with DS-01, it was further increased, but the difference was not statistically significant (<i>p ></i> 0.05). The number of mice used was as follows: 2N-vehicle/Ts65Dn-vehicle/2N-DS-01/Ts65Dn-DS-01 = 7/10/8/12. (F) The level of anti-Aβ40 IgG titers correlated with the Aβ40 level in the plasma of Ts65Dn mice treated with the DS-01. (Pearson r correlation 0.6, <i>p</i> = 0.04). The number of mice used was: Ts65Dn-DS-01 = 12. (G) An inverse correlation was found between the level of Aβ42 in the brain and in the plasma (Pearson r correlation -0.5 <i>p</i> = 0.012). The number of mice used was: Ts65Dn-DS-01 = 12. ns- non-significant, *—<i>p</i> < 0.05, **—<i>p</i> < 0.01. Error bars, SEM.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3151981, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/DS_01_immunization_resulted_in_a_trend_to_reduced_levels_of_A_42_and_A_40_in_the_Ts65Dn_brain_/3151981", "title"=>"DS-01 immunization resulted in a trend to reduced levels of Aβ42 and Aβ40 in the Ts65Dn brain.", "pos_in_sequence"=>5, "defined_type"=>1, "published_date"=>"2016-03-29 07:56:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/4910089"], "description"=>"<p>(A) Anti-mouse-Aβ40 and (B) Aβ42 IgG titers were detected in plasma of DS-01 immunized mice following the 2<sup>nd</sup> and the 4<sup>th</sup> injection. Significant titers remained as late as 40 days after the 6<sup>th</sup> injection. There was no significant difference between titers in 2N versus Ts65Dn mice. (C to F) Analysis of anti-mouse-Aβ40 IgG isotypes following the 4<sup>th</sup> immunization. (G) Anti mouse Aβ40 IgM titers were lower in Ts65Dn mice. (H to M) Analysis of anti-mouse-Aβ42 IgG isotypes following the 4<sup>th</sup> immunization. (N) Anti mouse Aβ42 IgM titers were lower in Ts65Dn mice. One-way ANOVA, Bonferroni's multiple comparison test *—<i>p</i> < 0.05; **—<i>p</i> < 0.01; ***—<i>p</i> < 0.001. Error bars, SEM. The number of mice was: 2N-vehicle/Ts65Dn-vehicle/2N-DS-01/Ts65Dn-DS-01 = 18/11/20/15.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3151951, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Anti_mouse_A_antibody_levels_in_2N_and_Ts65Dn_mice_immunized_with_either_vehicle_or_DS_01_/3151951", "title"=>"Anti-mouse Aβ antibody levels in 2N and Ts65Dn mice immunized with either vehicle or DS-01.", "pos_in_sequence"=>3, "defined_type"=>1, "published_date"=>"2016-03-29 07:56:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/4910041"], "description"=>"<div><p>In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased <i>APP</i> gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer’s disease (AD). At present, no treatment targets Aβ–related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1–15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS.</p></div>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3151924, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471", "stats"=>{"downloads"=>2, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/An_Anti_Amyloid_Vaccine_for_Treating_Cognitive_Deficits_in_a_Mouse_Model_of_Down_Syndrome/3151924", "title"=>"An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome", "pos_in_sequence"=>1, "defined_type"=>3, "published_date"=>"2016-03-29 07:56:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/4910164"], "description"=>"<p>(A) The area of ChAT+ cell bodies was significantly larger in Ts65Dn-DS-01 relative to Ts65Dn-vehicle treated mice (<i>p</i> = 0.03). (B) Number and <b>c</b> optical density of ChAT+ cells in medial septum were similar in DS-01-treated and vehicle-treated 2N and Ts65Dn mice. Two-tailed Student T test, *—<i>p</i> < 0.05. Error bars, SEM. The number of mice used was as follows: 2N- vehicle/Ts65Dn- vehicle/2N-DS-01/Ts65Dn-DS-01 = 4/4/4/4.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3152026, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471.g007", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Immunization_with_DS_01_prevented_the_atrophy_of_cholinergic_neurons_/3152026", "title"=>"Immunization with DS-01 prevented the atrophy of cholinergic neurons.", "pos_in_sequence"=>8, "defined_type"=>1, "published_date"=>"2016-03-29 07:56:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/4910134"], "description"=>"<p>(A) Western blot showing bands for APP and CTFs in brain samples from 2N and Ts65Dn mice. Tubulin was used as internal reference. The lanes are: 2N-vehicle (2, 6, 10, 13); Ts65Dn-vehicle (4, 8); 2N-DS-01 (1, 5, 9, 12, 15); Ts65Dn-DS-01 (3, 7, 11, 14). (B) Quantification of APP showed a higher level in Ts65Dn mice (although here it reached only borderline significance, <i>p</i> = 0.07). Following treatment with DS-01, no significant difference was observed in APP relative to the vehicle for either genotype (2N, vehicle vs DS-01, <i>p</i> = 0.9; Ts65Dn; vehicle vs DS-01, <i>p</i> = 0.4). (C) Quantitation of CTFs revealed significantly higher levels in T65Dn brains in both vehicle-treated and vaccine-treated mice (2N vehicle vs Ts65Dn vehicle, <i>p</i> = 0.01; 2N DS-01 vs Ts65Dn DS-01, <i>p</i> = 0.008). Following DS-01 treatment, no significant difference was observed in CTFs (2N, vehicle vs DS-01, <i>p</i> = 0.7; Ts65Dn; vehicle vs DS-01, <i>p</i> = 0.2). The number of mice used for APP and CTFs was: 2N- vehicle/Ts65Dn- vehicle/2N-DS-01/Ts65Dn-DS-01 = 7/5/8/8. (D) Quantification of α-CTF and (E) β-CTF levels in vehicle-treated and immunized mice. There was no significant effect of vaccine-treatment (α-CTFs: 2N, vehicle vs DS-01 <i>p</i> = 0.9; Ts65Dn, vehicle vs DS-01 <i>p =</i> 0.8.; β-CTF: 2N, vehicle vs DS-01 <i>p</i> = 0.9; Ts65Dn, vehicle vs DS-01 <i>p =</i> 0.9). The number of mice used was: 2N- vehicle/Ts65Dn- vehicle/2N-DS-01/Ts65Dn-DS-01 = 4/5/5/7. Error bars, SEM. All statistical analyses were performed using two-tailed Student T test #, <i>p</i> = 0.07, ns- non-significant, *—<i>p</i> < 0.05, **—<i>p</i> < 0.01.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3151996, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Vaccination_had_no_significant_effect_on_the_levels_of_APP_or_CTFs_/3151996", "title"=>"Vaccination had no significant effect on the levels of APP or CTFs.", "pos_in_sequence"=>6, "defined_type"=>1, "published_date"=>"2016-03-29 07:56:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/4910104"], "description"=>"<p>(A) Assessment of immunoreactivity against human and mouse Aβ. Different quantities of mouse or human Aβ were blotted with dilutions of plasma (1:100 and 1:1000). The vaccine-induced antibodies were specific to mouse Aβ. (B) Western blots of two homogenates from Ts65Dn (lane 1) and 2N brains (lane 2) comparing vaccine-induced plasma (green signals) and a commercial anti-Aβ antibody to the C-terminus of APP (red signals). Only the commercial APP C-terminal antibody allowed the detection of APP and CTF. Unidentified bands were also detected using each of the antibodies, but no overlapping bands were observed, best appreciated in the right panel at higher magnification. The brain samples loaded were: vehicle-treated Ts65Dn (lane 1), vehicle-treated 2N (lane 2), synthetic mouse Aβ (lane 3). (C) Western blots of homogenates from CHO or PC12 cells using vaccine-induced plasma and a commercial anti-Aβ antibody. (Left panel) Lysates of wild type CHO cells (lanes 1 and 3), or CHO cells transfected with APP (lanes 2 and 4), were probed with plasma (1:1000) (lanes 1 and 2) or with the APP C-terminal antibody (1:1000) (lanes 3 and 4). (Right panel) The lysates of PC12 cells transfected with GFP alone were probed with plasma (lanes 1 and 2), with the APP C-terminal antibody (lanes 5 and 6) or with anti-GFP antibody (lanes 9 and 10). The lysates of PC12 cells expressing C99/GFP probed with plasma (lanes 3 and 4), with the APP C-terminal antibody (lanes 7 and 8), or with anti-GFP antibody (lanes 11 and 12). There was no cross-reactivity of vaccine-induced plasma with full length APP or CTFs. (D) Varying amounts of recombinant C99 were blotted with the vaccine-induced plasma (green bands) or with a commercial anti-APP antibody (red band). Vaccine-induced plasma demonstrated sensitivity at least 30-fold less than the APP C-terminal antibody.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "contextual fear conditioning tests", "vaccinated Ts 65Dn mice", "neuropathological markers", "5 months", "Mouse Model", "Ts 65Dn mice", "Evidence points", "MPLA", "vaccine", "8 months", "basal forebrain cholinergic neurons", "treatment targets", "APP gene dose", "Cognitive Deficits", "mouse model", "β levels", "adjuvant monophosphoryl lipid", "novel object recognition", "DS", "memory deficits", "brain levels", "cholinergic neuron atrophy", "AD"], "article_id"=>3151966, "categories"=>["Biochemistry", "Neuroscience", "Immunology", "Science Policy", "Mental Health"], "users"=>["Pavel V. Belichenko", "Rime Madani", "Lorianne Rey-Bellet", "Maria Pihlgren", "Ann Becker", "Adeline Plassard", "Stephanie Vuillermot", "Valérie Giriens", "Rachel L. Nosheny", "Alexander M. Kleschevnikov", "Janice S. Valletta", "Sara K. S. Bengtsson", "Gordon R. Linke", "Michael T. Maloney", "David T. Hickman", "Pedro Reis", "Anne Granet", "Dorin Mlaki", "Maria Pilar Lopez-Deber", "Long Do", "Nishant Singhal", "Eliezer Masliah", "Matthew L. Pearn", "Andrea Pfeifer", "Andreas Muhs", "William C. Mobley"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0152471.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Characterization_of_vaccine_induced_plasma_immunoreactivity_/3151966", "title"=>"Characterization of vaccine-induced plasma immunoreactivity.", "pos_in_sequence"=>4, "defined_type"=>1, "published_date"=>"2016-03-29 07:56:56"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2016-01-01T00:00:00Z", "end_date"=>"2016-12-31T00:00:00Z", "subject_areas"=>[]}
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