Knockdown of pp32 Increases Histone Acetylation and Ameliorates Cognitive Deficits.
Knockdown of pp32 Increases Histone Acetylation and Ameliorates Cognitive Deficits.
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pp32 的敲低会增加组蛋白乙酰化并改善认知缺陷
DOI：
10.3389/fnagi.2017.00104
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发表时间：
2017
影响因子：
4.8
通讯作者：
Liu GP
中科院分区：
文献类型：
--
作者：
Feng Q;Chai GS;Wang ZH;Hu Y;Sun DS;Li XG;Ma RH;Li YR;Ke D;Wang JZ;Liu GP
衰老是老年人认知功能减退的原因之一，也是阿尔茨海默病的主要危险因素，然而，老年人并不都注定会发展成认知缺陷，这种老年人认知差异背后的分子机制尚不清楚。表观遗传修饰，特别是神经系统中的组蛋白乙酰化，在调节学习和记忆的基因表达方面发挥着关键作用。一种乙酰基转移酶抑制剂(INHAT)被报道通过组蛋白掩蔽机制抑制组蛋白乙酰化，pp32是INHAT复合体的关键成分。在本研究中，我们用Morris水迷宫将~18m龄小鼠分为认知正常组和认知受损组，发现认知受损老年小鼠海马区pp32水平显著升高。突触相关蛋白的mRNA和蛋白水平降低，树突复杂性降低，组蛋白乙酰化。通过突触相关蛋白的恢复、脊柱密度的增加和组蛋白乙酰化水平的提高，pp32基因的敲除拯救了认知受损老年小鼠的认知能力下降。我们的研究揭示了衰老相关认知障碍的一种新机制，表明抑制pp32可能是一种有前途的学习和记忆障碍的治疗方法。
Aging is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease, however, aging people are not all destined to develop into cognitive deficits, the molecular mechanisms underlying this difference in cognition of aging people are obscure. Epigenetic modifications, particularly histone acetylation in the nervous system, play a critical role in regulation of gene expression for learning and memory. An inhibitor of acetyltransferases (INHAT) is reported to suppress histone acetylation via a histone-masking mechanism, and pp32 is a key component of INHAT complex. In the present study, we divided ~18 m-old aged mice into the cognitive-normal and the cognitive-impaired group by Morris water maze, and found that pp32 level was significantly increased in the hippocampus of cognitive-impaired aged mice. The mRNA and protein levels of synaptic-associated proteins decreased with reduced dendrite complexity and histone acetylation. Knockdown of pp32 rescued cognitive decline in cognitive-impaired aged mice with restoration of synaptic-associated proteins, the increase of spine density and elevation of histone acetylation. Our study reveals a novel mechanism underlying the aging-associated cognitive disturbance, indicating that suppression of pp32 might represent a promising therapeutic approach for learning and memory impairments.