An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome.
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...
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Public Library of Science (PLoS)
2016-01-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Pavel V Belichenko |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e6e5615e619c41a0ad64eafb049c71c7 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-e6e5615e619c41a0ad64eafb049c71c72025-08-20T01:51:24ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01113e015247110.1371/journal.pone.0152471An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome.Pavel V BelichenkoRime MadaniLorianne Rey-BelletMaria PihlgrenAnn BeckerAdeline PlassardStephanie VuillermotValérie GiriensRachel L NoshenyAlexander M KleschevnikovJanice S VallettaSara K S BengtssonGordon R LinkeMichael T MaloneyDavid T HickmanPedro ReisAnne GranetDorin MlakiMaria Pilar Lopez-DeberLong DoNishant SinghalEliezer MasliahMatthew L PearnAndrea PfeiferAndreas MuhsWilliam C MobleyIn 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0152471&type=printable |
| spellingShingle | 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 An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome. PLoS ONE |
| title | An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome. |
| title_full | An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome. |
| title_fullStr | An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome. |
| title_full_unstemmed | An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome. |
| title_short | An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome. |
| title_sort | anti β amyloid vaccine for treating cognitive deficits in a mouse model of down syndrome |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0152471&type=printable |
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