Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models
Lewy body dementia (LBD) is an often misdiagnosed and mistreated neurodegenerative disorder clinically characterized by the emergence of neuropsychiatric symptoms followed by motor impairment. LBD falls within an undefined range between Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to th...
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MDPI AG
2023-10-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/10/2863 |
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| author | Melina J. Lim Suelen L. Boschen Aishe Kurti Monica Castanedes Casey Virginia R. Phillips John D. Fryer Dennis Dickson Karen R. Jansen-West Leonard Petrucelli Marion Delenclos Pamela J. McLean |
| author_facet | Melina J. Lim Suelen L. Boschen Aishe Kurti Monica Castanedes Casey Virginia R. Phillips John D. Fryer Dennis Dickson Karen R. Jansen-West Leonard Petrucelli Marion Delenclos Pamela J. McLean |
| author_sort | Melina J. Lim |
| collection | DOAJ |
| description | Lewy body dementia (LBD) is an often misdiagnosed and mistreated neurodegenerative disorder clinically characterized by the emergence of neuropsychiatric symptoms followed by motor impairment. LBD falls within an undefined range between Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the potential pathogenic synergistic effects of tau, beta-amyloid (Aβ), and alpha-synuclein (αsyn). A lack of reliable and relevant animal models hinders the elucidation of the molecular characteristics and phenotypic consequences of these interactions. Here, the goal was to evaluate whether the viral-mediated overexpression of αsyn in adult hTau and APP/PS1 mice or the overexpression of tau in Line 61 hThy1-αsyn mice resulted in pathology and behavior resembling LBD. The transgenes were injected intravenously via the tail vein using AAV-PHP.eB in 3-month-old hThy1-αsyn, hTau, or APP/PS1 mice that were then aged to 6-, 9-, and 12-months-old for subsequent phenotypic and histological characterization. Although we achieved the widespread expression of αsyn in hTau and tau in hThy1-αsyn mice, no αsyn pathology in hTau mice and only mild tau pathology in hThy1-αsyn mice was observed. Additionally, cognitive, motor, and limbic behavior phenotypes were not affected by overexpression of the transgenes. Furthermore, our APP/PS1 mice experienced premature deaths starting at 3 months post-injection (MPI), therefore precluding further analyses at later time points. An evaluation of the remaining 3-MPI indicated no αsyn pathology or cognitive and motor behavioral changes. Taken together, we conclude that the overexpression of αsyn in hTau and APP/PS1 mice and tau in hThy1-αsyn mice does not recapitulate the behavioral and neuropathological phenotypes observed in LBD. |
| first_indexed | 2024-03-10T21:24:17Z |
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| id | doaj.art-3baa64b6498643d1a8787bb092b331cf |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T21:24:17Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-3baa64b6498643d1a8787bb092b331cf2023-11-19T15:48:11ZengMDPI AGBiomedicines2227-90592023-10-011110286310.3390/biomedicines11102863Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse ModelsMelina J. Lim0Suelen L. Boschen1Aishe Kurti2Monica Castanedes Casey3Virginia R. Phillips4John D. Fryer5Dennis Dickson6Karen R. Jansen-West7Leonard Petrucelli8Marion Delenclos9Pamela J. McLean10Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USADepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USALewy body dementia (LBD) is an often misdiagnosed and mistreated neurodegenerative disorder clinically characterized by the emergence of neuropsychiatric symptoms followed by motor impairment. LBD falls within an undefined range between Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the potential pathogenic synergistic effects of tau, beta-amyloid (Aβ), and alpha-synuclein (αsyn). A lack of reliable and relevant animal models hinders the elucidation of the molecular characteristics and phenotypic consequences of these interactions. Here, the goal was to evaluate whether the viral-mediated overexpression of αsyn in adult hTau and APP/PS1 mice or the overexpression of tau in Line 61 hThy1-αsyn mice resulted in pathology and behavior resembling LBD. The transgenes were injected intravenously via the tail vein using AAV-PHP.eB in 3-month-old hThy1-αsyn, hTau, or APP/PS1 mice that were then aged to 6-, 9-, and 12-months-old for subsequent phenotypic and histological characterization. Although we achieved the widespread expression of αsyn in hTau and tau in hThy1-αsyn mice, no αsyn pathology in hTau mice and only mild tau pathology in hThy1-αsyn mice was observed. Additionally, cognitive, motor, and limbic behavior phenotypes were not affected by overexpression of the transgenes. Furthermore, our APP/PS1 mice experienced premature deaths starting at 3 months post-injection (MPI), therefore precluding further analyses at later time points. An evaluation of the remaining 3-MPI indicated no αsyn pathology or cognitive and motor behavioral changes. Taken together, we conclude that the overexpression of αsyn in hTau and APP/PS1 mice and tau in hThy1-αsyn mice does not recapitulate the behavioral and neuropathological phenotypes observed in LBD.https://www.mdpi.com/2227-9059/11/10/2863Lewy body dementiaLewy bodyalpha-synucleintauamyloid betamouse model |
| spellingShingle | Melina J. Lim Suelen L. Boschen Aishe Kurti Monica Castanedes Casey Virginia R. Phillips John D. Fryer Dennis Dickson Karen R. Jansen-West Leonard Petrucelli Marion Delenclos Pamela J. McLean Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models Biomedicines Lewy body dementia Lewy body alpha-synuclein tau amyloid beta mouse model |
| title | Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models |
| title_full | Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models |
| title_fullStr | Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models |
| title_full_unstemmed | Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models |
| title_short | Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models |
| title_sort | investigating the pathogenic interplay of alpha synuclein tau and amyloid beta in lewy body dementia insights from viral mediated overexpression in transgenic mouse models |
| topic | Lewy body dementia Lewy body alpha-synuclein tau amyloid beta mouse model |
| url | https://www.mdpi.com/2227-9059/11/10/2863 |
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