Activation of GSK-3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats.
Activation of GSK-3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats.
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DOI：
10.1111/jcmm.13262
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发表时间：
2017-12
影响因子：
5.3
通讯作者：
Wang JZ
中科院分区：
文献类型：
--
作者：
Wang Y;Tian Q;Liu EJ;Zhao L;Song J;Liu XA;Ren QG;Jiang X;Zeng J;Yang YT;Wang JZ
胆碱能损害是阿尔茨海默病（AD）的早期标志物，但其机制尚未完全清楚。我们研究了糖原合成酶激酶-3（GSK-3）激活对Meynert基底核（NBM）和额叶皮质（胆碱能富集区）胆碱能稳态的影响。我们通过侧脑室输注Wortmannin（WT）和GF-109203 X（GFX）激活GSK-3，分别是磷酸肌醇-3激酶（PI 3-K）和蛋白激酶C（PKC）的抑制剂，并通过抑制胆碱乙酰转移酶（ChAT）而不是调节乙酰胆碱酯酶（AChE）来显著降低乙酰胆碱（ACh）水平。神经元轴突运输中断，ChAT积聚发生在NBM和额叶皮质，伴有tau蛋白和神经丝的过度磷酸化。此外，NBM中ChAT的表达降低，这是由于核因子-κB/p100被切割成p52转位到细胞核中，从而降低ChAT mRNA水平。胆碱能功能障碍可以通过GSK-3的过表达来模拟，并通过同时给予GSK-3的抑制剂LiCl或SB 216763来挽救。我们的数据揭示了可能导致AD患者胆碱能损害的分子机制。
The cholinergic impairment is an early marker in Alzheimer's disease (AD), while the mechanisms are not fully understood. We investigated here the effects of glycogen synthase kinse‐3 (GSK‐3) activation on the cholinergic homoeostasis in nucleus basalis of Meynert (NBM) and frontal cortex, the cholinergic enriched regions. We activated GSK‐3 by lateral ventricular infusion of wortmannin (WT) and GF‐109203X (GFX), the inhibitors of phosphoinositol‐3 kinase (PI3‐K) and protein kinase C (PKC), respectively, and significantly decreased the acetylcholine (ACh) level via inhibiting choline acetyl transferase (ChAT) rather than regulating acetylcholinesterase (AChE). Neuronal axonal transport was disrupted and ChAT accumulation occurred in NBM and frontal cortex accompanied with hyperphosphorylation of tau and neurofilaments. Moreover, ChAT expression decreased in NBM attributing to cleavage of nuclear factor‐κB/p100 into p52 for translocation into nucleus to lower ChAT mRNA level. The cholinergic dysfunction could be mimicked by overexpression of GSK‐3 and rescued by simultaneous administration of LiCl or SB216763, inhibitors of GSK‐3. Our data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients.
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影响因子：
4.7
作者：
Hawkes, C;Jhamandas, JH;Kar, S
通讯作者：
Kar, S
影响因子：
2.4
作者：
Prabhakar V;Gupta D;Kanade P;Radhakrishnan M
通讯作者：
Radhakrishnan M
影响因子：
8.2
作者：
Rao, R.;Hao, C. -M.;Breyer, M. D.
通讯作者：
Breyer, M. D.
DOI：
10.1073/pnas.93.7.2719
发表时间：
1996-04-02
影响因子：
11.1
作者：
Hoshi, M;Takashima, A;Imahori, K
通讯作者：
Imahori, K
影响因子：
3.5
作者：
ISHIGURO, K;SHIRATSUCHI, A;IMAHORI, K
通讯作者：
IMAHORI, K