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AAV9 介导的 Cdk5 抑制肽减少过度磷酸化的 tau 并减轻 p25 在脑中过表达引起的炎症和行为改变。

AAV9-Mediated Cdk5 Inhibitory Peptide Reduces Hyperphosphorylated Tau and Inflammation and Ameliorates Behavioral Changes Caused by Overexpression of p25 in the Brain.

机构信息

Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China.

Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, China.

出版信息

J Alzheimers Dis. 2019;70(2):573-585. doi: 10.3233/JAD-190099.

Abstract

BACKGROUND

Under stress stimulation, p25 is generated by cleavage of p35 and acts as an activator of cyclin-dependent kinase 5 (Cdk5) like p35. Unlike Cdk5/p35, which is important for brain development, aberrant activity of Cdk5/p25 plays a pathological role in neurodegenerative diseases, such as Alzheimer's disease, by inducing hyperphosphorylation of downstream substrates related to pathological progression. A truncated fragment of the c-terminus of p35, the Cdk5 inhibitory peptide (CIP), selectively inhibits Cdk5/ p25 activity in cultured neurons and in CIP/p25 tetra-transgenic mice.

OBJECTIVE

First, we aimed to establish a p25 overexpression adult mouse model, then to evaluate whether CIP delivered by adeno-associated virus serotype 9 (AAV9) can ameliorate neuronal toxicity induced by p25.

METHODS

The p25 overexpression mouse model was established by intracerebroventricular (i.c.v.) injection of AAV8-GFP-p25 in 8-week-old mice. One month later, these mice were i.c.v. injected with AAV9-CIP-T2A-mCherry or AAV9 vector as control. Pathological and behavioral changes were assessed 3-months post-injection in all mice.

RESULTS

The p25 overexpression mice displayed hyperphosphorylation of tau at multiple sites, activation of astrocytes, and elevated inflammatory factors, including IL-1 and TNF-α, which were significantly decreased by the administration of CIP. However, Aβ deposition and microgliosis were not obvious in p25 overexpression mice. In addition, a significant learning decline and anxiety-like behavior were induced by p25 toxicity, and CIP treatment improved learning ability in p25 mice.

CONCLUSION

AAV-mediated p25 overexpression mouse model is easy to construct to study p25-induced neuronal toxicity. Application of CIP after p25 insult reverses the pathological changes and behavioral abnormalities.

摘要

背景

在应激刺激下,p25 通过切割 p35 产生,其作用类似于 p35 的有丝分裂原激活蛋白激酶 5(Cdk5)激活剂。与对大脑发育很重要的 Cdk5/p35 不同,Cdk5/p25 的异常活性在神经退行性疾病中发挥病理性作用,如阿尔茨海默病,通过诱导与病理进展相关的下游底物的过度磷酸化。p35 C 端的截断片段,即 Cdk5 抑制肽(CIP),在培养神经元和 CIP/p25 四转基因小鼠中选择性抑制 Cdk5/p25 活性。

目的

首先,我们旨在建立 p25 过表达成年小鼠模型,然后评估腺相关病毒血清型 9(AAV9)递送的 CIP 是否可以改善 p25 诱导的神经元毒性。

方法

通过侧脑室(i.c.v.)注射 AAV8-GFP-p25 在 8 周龄小鼠中建立 p25 过表达小鼠模型。一个月后,这些小鼠通过 i.c.v. 注射 AAV9-CIP-T2A-mCherry 或 AAV9 载体作为对照。所有小鼠在注射后 3 个月评估病理和行为变化。

结果

p25 过表达小鼠表现出 tau 多个位点的过度磷酸化、星形胶质细胞激活和炎症因子升高,包括 IL-1 和 TNF-α,这些因子在 CIP 给药后显著降低。然而,p25 过表达小鼠中没有明显的 Aβ 沉积和小胶质细胞增生。此外,p25 毒性诱导了明显的学习能力下降和焦虑样行为,CIP 治疗改善了 p25 小鼠的学习能力。

结论

AAV 介导的 p25 过表达小鼠模型易于构建,用于研究 p25 诱导的神经元毒性。p25 损伤后应用 CIP 可逆转病理变化和行为异常。

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