JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model.
JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model.
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作者：
c-Jun N-末端激酶（JNK）是一个蛋白质家族，一旦被应激刺激激活，就可以改变神经元的功能和存活。JNK级联在突触后神经元隔室中起着至关重要的作用，通过改变其结构组织，并导致最坏的情况下，神经元通讯的整体损伤。越来越多的证据表明，突触损伤是阿尔茨海默病（AD）的第一个神经退行性事件。为了更好地阐明这一机制，我们在代表人类AD症状进展的三个选定时间点纵向研究了5xFAD小鼠。我们测试小鼠的认知能力，通过使用径向臂水迷宫（RAWM）与生化评价突触后富集的蛋白质部分和总皮质实质平行。我们发现，5xFAD小鼠在3.5个月龄时在突触后富集的蛋白质组分中呈现出强烈的JNK激活。这种JNK激活与突触后密度区的结构改变相关，并且与疾病早期阶段的记忆障碍相关，记忆障碍逐渐下降，导致细胞死亡。这些发现为JNK作为早期神经退行性变的关键参与者以及作为开发能够解决AD病理早期突触损伤的新化合物的重要治疗靶点的未来研究铺平了道路。
The c-Jun N-terminal kinases (JNKs) are a family of proteins that, once activated by stress stimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in the post-synaptic neuronal compartment by altering its structural organization and leading, at worst, to an overall impairment of neuronal communication. Increasing evidence suggests that synaptic impairment is the first neurodegenerative event in Alzheimer’s disease (AD). To better elucidate this mechanism, we longitudinally studied 5xFAD mice at three selected time points representative of human AD symptom progression. We tested the mice cognitive performance by using the radial arm water maze (RAWM) in parallel with biochemical evaluations of post-synaptic enriched protein fraction and total cortical parenchyma. We found that 5xFAD mice presented a strong JNK activation at 3.5 months of age in the post-synaptic enriched protein fraction. This JNK activation correlates with a structural alteration of the post-synaptic density area and with memory impairment at this early stage of the disease that progressively declines to cause cell death. These findings pave the way for future studies on JNK as a key player in early neurodegeneration and as an important therapeutic target for the development of new compounds able to tackle synaptic impairment in the early phase of AD pathology.
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影响因子：
4.7
作者：
Brenner M;Messing A
通讯作者：
Messing A
DOI：
10.1083/jcb.200301115
发表时间：
2003-10-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee MS;Kao SC;Lemere CA;Xia W;Tseng HC;Zhou Y;Neve R;Ahlijanian MK;Tsai LH
通讯作者：
Tsai LH
影响因子：
4.2
作者：
Brenner M;Messing A;Olsen ML
通讯作者：
Olsen ML
影响因子：
4.2
作者：
Benzing, WC;Wujek, JR;Brunden, KR
通讯作者：
Brunden, KR
影响因子：
6.1
作者：
Musi CA;Bonadonna C;Borsello T
通讯作者：
Borsello T