Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models.
Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models.
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DOI：
10.3390/biomedicines11102863
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发表时间：
2023-10-22
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
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路易体痴呆（LBD）是一种常被误诊和误治的神经退行性疾病，其临床特征是出现神经精神症状并伴有运动障碍。由于tau、β -淀粉样蛋白（Aβ）和α -突触核蛋白（αsyn）的潜在致病协同作用，LBD属于阿尔茨海默病（AD）和帕金森病（PD）之间的未明确范围。缺乏可靠和相关的动物模型阻碍了这些相互作用的分子特征和表型后果的阐明。本研究的目的是评估成年hTau和APP/PS1小鼠中病毒介导的αsyn过表达或Line 61 hThy1-αsyn小鼠中tau过表达是否会导致类似LBD的病理和行为。用AAV-PHP经尾静脉静脉注射转基因。3月龄hThy1-αsyn、hTau或APP/PS1小鼠中存在eB，然后将这些小鼠培养至6、9和12月龄，进行随后的表型和组织学表征。虽然我们在hTau和hThy1-αsyn小鼠中实现了αsyn的广泛表达，但在hTau小鼠中未观察到αsyn病理，在hThy1-αsyn小鼠中仅观察到轻微的tau病理。此外，认知、运动和边缘行为表型不受转基因过表达的影响。此外，我们的APP/PS1小鼠在注射后3个月（MPI）开始出现过早死亡，因此排除了在以后的时间点进行进一步分析。剩余3-MPI的评估显示没有αsyn病理或认知和运动行为的改变。综上所述，我们得出结论，αsyn在hTau和APP/PS1小鼠中的过表达，以及tau在hThy1-αsyn小鼠中的过表达，并不能概括在LBD中观察到的行为和神经病理表型。
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.
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