Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice
Abstract Background Alzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-019-0556-2 |
| _version_ | 1819077060176379904 |
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| author | Hayk Davtyan Armine Hovakimyan Sepideh Kiani Shabestari Tatevik Antonyan Morgan A. Coburn Karen Zagorski Gor Chailyan Irina Petrushina Olga Svystun Emma Danhash Nikolai Petrovsky David H. Cribbs Michael G. Agadjanyan Mathew Blurton-Jones Anahit Ghochikyan |
| author_facet | Hayk Davtyan Armine Hovakimyan Sepideh Kiani Shabestari Tatevik Antonyan Morgan A. Coburn Karen Zagorski Gor Chailyan Irina Petrushina Olga Svystun Emma Danhash Nikolai Petrovsky David H. Cribbs Michael G. Agadjanyan Mathew Blurton-Jones Anahit Ghochikyan |
| author_sort | Hayk Davtyan |
| collection | DOAJ |
| description | Abstract Background Alzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aβ or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aβ and tau might be needed for effective disease modification. Methods A combinatorial vaccination approach was designed to concurrently target both Aβ and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aβ and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aβ and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays. Results T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of bigenic T5x mice. Conclusions AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD. |
| first_indexed | 2024-12-21T18:51:11Z |
| format | Article |
| id | doaj.art-5972ea523f564c8fabf6e4f05a708840 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-21T18:51:11Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-5972ea523f564c8fabf6e4f05a7088402022-12-21T18:53:45ZengBMCAlzheimer’s Research & Therapy1758-91932019-12-0111111310.1186/s13195-019-0556-2Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic miceHayk Davtyan0Armine Hovakimyan1Sepideh Kiani Shabestari2Tatevik Antonyan3Morgan A. Coburn4Karen Zagorski5Gor Chailyan6Irina Petrushina7Olga Svystun8Emma Danhash9Nikolai Petrovsky10David H. Cribbs11Michael G. Agadjanyan12Mathew Blurton-Jones13Anahit Ghochikyan14Department of Molecular Immunology, Institute for Molecular MedicineDepartment of Molecular Immunology, Institute for Molecular MedicineSue and Bill Gross Stem Cell Research Center, University of California, IrvineDepartment of Molecular Immunology, Institute for Molecular MedicineSue and Bill Gross Stem Cell Research Center, University of California, IrvineDepartment of Molecular Immunology, Institute for Molecular MedicineDepartment of Molecular Immunology, Institute for Molecular MedicineInstitute for Memory Impairments and Neurological Disorders, University of California, IrvineDepartment of Molecular Immunology, Institute for Molecular MedicineInstitute for Memory Impairments and Neurological Disorders, University of California, IrvineFlinders University and Vaxine Pty LtdInstitute for Memory Impairments and Neurological Disorders, University of California, IrvineDepartment of Molecular Immunology, Institute for Molecular MedicineInstitute for Memory Impairments and Neurological Disorders, University of California, IrvineDepartment of Molecular Immunology, Institute for Molecular MedicineAbstract Background Alzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aβ or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aβ and tau might be needed for effective disease modification. Methods A combinatorial vaccination approach was designed to concurrently target both Aβ and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aβ and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aβ and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays. Results T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of bigenic T5x mice. Conclusions AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD.https://doi.org/10.1186/s13195-019-0556-2MultiTEP platformAlzheimer’s diseaseProtein epitope vaccineAntibodyAdjuvantBigenic mice |
| spellingShingle | Hayk Davtyan Armine Hovakimyan Sepideh Kiani Shabestari Tatevik Antonyan Morgan A. Coburn Karen Zagorski Gor Chailyan Irina Petrushina Olga Svystun Emma Danhash Nikolai Petrovsky David H. Cribbs Michael G. Agadjanyan Mathew Blurton-Jones Anahit Ghochikyan Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice Alzheimer’s Research & Therapy MultiTEP platform Alzheimer’s disease Protein epitope vaccine Antibody Adjuvant Bigenic mice |
| title | Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice |
| title_full | Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice |
| title_fullStr | Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice |
| title_full_unstemmed | Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice |
| title_short | Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice |
| title_sort | testing a multitep based combination vaccine to reduce aβ and tau pathology in tau22 5xfad bigenic mice |
| topic | MultiTEP platform Alzheimer’s disease Protein epitope vaccine Antibody Adjuvant Bigenic mice |
| url | https://doi.org/10.1186/s13195-019-0556-2 |
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