人源野生型 TDP-43 的过表达导致 CAMKII-tTa 转基因小鼠模型中海马可塑性损伤和行为缺陷。
Overexpression of human wtTDP-43 causes impairment in hippocampal plasticity and behavioral deficits in CAMKII-tTa transgenic mouse model.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
出版信息
Mol Cell Neurosci. 2020 Jan;102:103418. doi: 10.1016/j.mcn.2019.103418. Epub 2019 Nov 6.
AIMS
The current study utilizes the adeno-associated viral gene transfer system in the CAMKIIα-tTA mouse model to overexpress human wild type TDP-43 (wtTDP-43) and α-synuclein (α-Syn) proteins. The co-existence of these proteins is evident in the pathology of neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD), Parkinson disease (PD), and dementia with Lewy bodies (DLB).
METHODS
The novel bicistronic recombinant adeno-associated virus (rAAV) serotype 9 drives wtTDP-43 and α-Syn expression in the hippocampus via "TetO" CMV promoter. Behavior, electrophysiology, and biochemical and histological assays were used to validate neuropathology.
RESULTS
We report that overexpression of wtTDP-43 but not α-Syn contributes to hippocampal CA2-specific pyramidal neuronal loss and overall hippocampal atrophy. Further, we report a reduction of hippocampal long-term potentiation and decline in learning and memory performance of wtTDP-43 expressing mice. Elevated wtTDP-43 levels induced selective degeneration of Purkinje cell protein 4 (PCP-4) positive neurons while both wtTDP-43 and α-Syn expression reduced subsets of the glutamate receptor expression in the hippocampus.
CONCLUSIONS
Overall, our findings suggest the significant vulnerability of hippocampal neurons toward elevated wtTDP-43 levels possibly via PCP-4 and GluR-dependent calcium signaling pathways. Further, we report that wtTDP-43 expression induced selective CA2 subfield degeneration, contributing to the deterioration of the hippocampal-dependent cognitive phenotype.
目的
本研究利用腺相关病毒基因转移系统在 CAMKIIα-tTA 小鼠模型中过表达人野生型 TDP-43（wtTDP-43）和α-突触核蛋白（α-Syn）。这些蛋白质的共存存在于神经退行性疾病的病理学中，如额颞叶变性（FTLD）、帕金森病（PD）和路易体痴呆（DLB）。
方法
新型双顺反子重组腺相关病毒（rAAV）血清型 9 通过“TetO”CMV 启动子在海马体中驱动 wtTDP-43 和 α-Syn 的表达。行为、电生理学、生化和组织学检测用于验证神经病理学。
结果
我们报告说，wtTDP-43 的过表达而不是 α-Syn 的过表达导致海马体 CA2 特异性锥体神经元丢失和海马体整体萎缩。此外，我们报告了 wtTDP-43 表达小鼠的海马体长时程增强作用降低和学习记忆能力下降。wtTDP-43 水平的升高诱导了 Purkinje 细胞蛋白 4（PCP-4）阳性神经元的选择性退化，而 wtTDP-43 和 α-Syn 的表达降低了海马体中谷氨酸受体表达的子集。
结论
总的来说，我们的研究结果表明，海马体神经元对升高的 wtTDP-43 水平具有显著的易感性，可能通过 PCP-4 和 GluR 依赖的钙信号通路。此外，我们报告称，wtTDP-43 表达诱导了 CA2 亚区的选择性退化，导致了海马体依赖的认知表型的恶化。
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