Molecular mechanisms of environmental enrichment: impairments in Akt/GSK3β, neurotrophin-3 and CREB signaling.
Molecular mechanisms of environmental enrichment: impairments in Akt/GSK3β, neurotrophin-3 and CREB signaling.
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DOI：
10.1371/journal.pone.0064460
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lazarov O
中科院分区：
文献类型：
--
作者：
Hu YS;Long N;Pigino G;Brady ST;Lazarov O
小鼠在复杂环境中的经历增强了野生型和转基因小鼠携带家族性阿尔茨海默病（FAD）相关APPswe/PS1ΔE9的海马神经发生和突触可塑性。在FAD小鼠中，这种经历也降低了tau过度磷酸化和低聚β-淀粉样蛋白的水平。虽然环境富集对大脑可塑性和神经病理学有显著影响，但这些影响的分子机制尚不清楚。在野生型而非FAD小鼠中，环境富集可上调Akt通路，导致糖原合成酶激酶3β (GSK3β)下调。野生型和FAD小鼠海马中包括脑源性神经营养因子（BDNF）和神经生长因子（NGF）在内的几种神经营养信号通路均被激活，并且这种激活伴随着BDNF受体酪氨酸激酶B （TrkB）的上调。有趣的是，神经营养因子-3 （NT-3）在野生型小鼠的大脑中上调，而FAD小鼠的大脑中没有上调，而胰岛素生长因子-1 （IGF-1）仅在FAD小鼠的大脑中上调。神经营养因子的上调伴随着海马中n -甲基- d -天冬氨酸（NMDA）受体在环境富集后的增加。最重要的是，我们观察到野生型和FAD小鼠海马中cAMP反应元件结合（CREB）转录物水平在环境富集后显著增加。然而，CREB磷酸化是启动学习和记忆所需基因转录的关键步骤，它发生在野生型小鼠的海马体中，而不是FAD小鼠。这些结果表明，野生型小鼠在复杂环境中的经历上调了海马中在学习和记忆中起重要作用的关键信号。然而，在FAD小鼠中，其中一些通路受损，不能通过环境富集来挽救。
Experience of mice in a complex environment enhances neurogenesis and synaptic plasticity in the hippocampus of wild type and transgenic mice harboring familial Alzheimer's disease (FAD)-linked APPswe/PS1ΔE9. In FAD mice, this experience also reduces levels of tau hyperphosphorylation and oligomeric β-amyloid. Although environmental enrichment has significant effects on brain plasticity and neuropathology, the molecular mechanisms underlying these effects are unknown. Here we show that environmental enrichment upregulates the Akt pathway, leading to the downregulation of glycogen synthase kinase 3β (GSK3β), in wild type but not FAD mice. Several neurotrophic signaling pathways are activated in the hippocampus of both wild type and FAD mice, including brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), and this increase is accompanied by the upregulation of the BDNF receptor, tyrosine kinase B (TrkB). Interestingly, neurotrophin-3 (NT-3) is upregulated in the brains of wild type mice but not FAD mice, while insulin growth factor-1 (IGF-1) is upregulated exclusively in the brains of FAD mice. Upregulation of neurotrophins is accompanied by the increase of N-Methyl-D-aspartic acid (NMDA) receptors in the hippocampus following environmental enrichment. Most importantly, we observed a significant increase in levels of cAMP response element- binding (CREB) transcripts in the hippocampus of wild type and FAD mice following environmental enrichment. However, CREB phosphorylation, a critical step for the initiation of learning and memory-required gene transcription, takes place in the hippocampus of wild type but not of FAD mice. These results suggest that experience of wild type mice in a complex environmental upregulates critical signaling that play a major role in learning and memory in the hippocampus. However, in FAD mice, some of these pathways are impaired and cannot be rescued by environmental enrichment.
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DOI：
10.1073/pnas.1012851108
发表时间：
2010-12-28
影响因子：
11.1
作者：
Caccamo, Antonella;Maldonado, Monica A.;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
影响因子：
5.3
作者：
Adlard, PA;Perreau, VM;Cotman, CW
通讯作者：
Cotman, CW
影响因子：
4.2
作者：
Adlard, PA;Perreau, VM;Cotman, CW
通讯作者：
Cotman, CW
DOI：
10.1007/bf02815006
发表时间：
1996-10-01
期刊：
MOLECULAR AND CHEMICAL NEUROPATHOLOGY
影响因子：
--
作者：
Baum, L;Hansen, L;Saitoh, T
通讯作者：
Saitoh, T
影响因子：
2.1
作者：
Ferrer, I.;Gomez-Isla, T.;Avila, J.
通讯作者：
Avila, J.