Overexpression of human wtTDP-43 causes impairment in hippocampal plasticity and behavioral deficits in CAMKII-tTa transgenic mouse model.
Overexpression of human wtTDP-43 causes impairment in hippocampal plasticity and behavioral deficits in CAMKII-tTa transgenic mouse model.
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DOI：
10.1016/j.mcn.2019.103418
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Selenica MB
中科院分区：
文献类型：
--
作者：
Quadri Z;Johnson N;Zamudio F;Miller A;Peters M;Smeltzer S;Hunt JB Jr;Housley SB;Brown B;Kraner S;Norris CM;Nash K;Weeber E;Lee DC;Selenica MB
目前的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)。这些蛋白的共存在神经退行性疾病的病理中很明显，如额颞叶变性(FTLD)、帕金森病(PD)和路易体痴呆(DLB)。新的双顺反子重组腺相关病毒血清9型通过“Teto”巨细胞病毒启动子在海马区驱动wtTDP-43和α-Syn的表达。通过行为学、电生理学、生化和组织学分析来验证神经病理学。我们报告了wtTDP-43的过度表达而不是α-Syn的过度表达导致了海马区特异性锥体神经元的丢失和整个海马区的萎缩。此外，我们报告了表达wtTDP-43的小鼠海马区长时程增强的减少和学习和记忆能力的下降。WtTDP-43水平升高导致浦肯野细胞蛋白4(PCP-4)阳性神经元选择性变性，而wtTDP-43和α-Syn表达均减少海马区谷氨酸受体亚群的表达。总体而言，我们的发现表明，海马神经元对wtTDP-43水平升高的显著脆弱性可能是通过PCP-4和Glu依赖的钙信号通路实现的。此外，我们报告了wtTDP-43的表达诱导了选择性的CA2亚区变性，导致了海马依赖的认知表型的恶化。
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). 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. 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. 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.
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影响因子：
5.3
作者：
Decressac, M.;Mattsson, B.;Bjorklund, A.
通讯作者：
Bjorklund, A.
影响因子：
16.2
作者：
Chevaleyre V;Siegelbaum SA
通讯作者：
Siegelbaum SA
影响因子：
1.7
作者：
Georgievska, B;Kirik, D;Björklund, A
通讯作者：
Björklund, A
影响因子：
38.1
作者：
Frisoni, Giovanni B.;Fox, Nick C.;Jack, Clifford R., Jr.;Scheltens, Philip;Thompson, Paul M.
通讯作者：
Thompson, Paul M.
DOI：
10.1097/nen.0b013e3181633526
发表时间：
2008-02-01
影响因子：
3.2
作者：
Alafuzoff, Irina;Parkkinen, Laura;Kretzschmar, Hans
通讯作者：
Kretzschmar, Hans