Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Lim, Melina J., Boschen, Suelen L., Kurti, Aishe, Castanedes Casey, Monica, Phillips, Virginia R., Fryer, John D., Dickson, Dennis, Jansen-West, Karen R., Petrucelli, Leonard, Delenclos, Marion, McLean, Pamela J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10604054/
https://www.ncbi.nlm.nih.gov/pubmed/37893236
http://dx.doi.org/10.3390/biomedicines11102863
_version_ 1785126743991910400
author Lim, Melina J.
Boschen, Suelen L.
Kurti, Aishe
Castanedes Casey, Monica
Phillips, Virginia R.
Fryer, John D.
Dickson, Dennis
Jansen-West, Karen R.
Petrucelli, Leonard
Delenclos, Marion
McLean, Pamela J.
author_facet Lim, Melina J.
Boschen, Suelen L.
Kurti, Aishe
Castanedes Casey, Monica
Phillips, Virginia R.
Fryer, John D.
Dickson, Dennis
Jansen-West, Karen R.
Petrucelli, Leonard
Delenclos, Marion
McLean, Pamela J.
author_sort Lim, Melina J.
collection PubMed
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.
format Online
Article
Text
id pubmed-10604054
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-106040542023-10-28 Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models Lim, Melina J. Boschen, Suelen L. Kurti, Aishe Castanedes Casey, Monica Phillips, Virginia R. Fryer, John D. Dickson, Dennis Jansen-West, Karen R. Petrucelli, Leonard Delenclos, Marion McLean, Pamela J. Biomedicines Article 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. MDPI 2023-10-22 /pmc/articles/PMC10604054/ /pubmed/37893236 http://dx.doi.org/10.3390/biomedicines11102863 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lim, Melina J.
Boschen, Suelen L.
Kurti, Aishe
Castanedes Casey, Monica
Phillips, Virginia R.
Fryer, John D.
Dickson, Dennis
Jansen-West, Karen R.
Petrucelli, Leonard
Delenclos, Marion
McLean, Pamela J.
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 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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10604054/
https://www.ncbi.nlm.nih.gov/pubmed/37893236
http://dx.doi.org/10.3390/biomedicines11102863
work_keys_str_mv AT limmelinaj investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT boschensuelenl investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT kurtiaishe investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT castanedescaseymonica investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT phillipsvirginiar investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT fryerjohnd investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT dicksondennis investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT jansenwestkarenr investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT petrucellileonard investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT delenclosmarion investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels
AT mcleanpamelaj investigatingthepathogenicinterplayofalphasynucleintauandamyloidbetainlewybodydementiainsightsfromviralmediatedoverexpressionintransgenicmousemodels