TIMP-1: a key cytokine released from activated astrocytes protects neurons and ameliorates cognitive behaviours in a rodent model of Alzheimer’s disease,Brain, Behavior, and Immunity

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TIMP-1: a key cytokine released from activated astrocytes protects neurons and ameliorates cognitive behaviours in a rodent model of Alzheimer’s disease
Brain, Behavior, and Immunity ( IF 8.8 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.bbi.2020.03.014
Pampa Saha ₁ , Sukanya Sarkar ₁ , Ramesh Kumar Paidi ₁ , Subhas C Biswas ₁

Affiliation

Alzheimer's disease (AD) is characterized by two pathologic species, extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. Astrocytes that maintain normal homeostasis in the brain undergo a set of molecular, cellular and functional changes called reactive astrogliosis in various neurological diseases including AD. It is hypothesized that reactive astrocytes initially tend to protect neurons by reducing Aβ load and by secreting a plethora of cytokines, however, their functions have only been poorly investigated. Our studies on the kinetics of activation of cortical astrocytes following Aβ-exposure revealed significant level of activation as early as in 6 h. The astrocyte conditioned medium (ACM) from 6 h Aβ-treated astrocytes (Aβ-ACM) provided significant neuroprotection of cultured cortical neurons against Aβ insults. Analysis of the secreted proteins in Aβ-ACM revealed a marked increase of Tissue inhibitor of Metalloproteinase-1(TIMP-1) within 6 h. Interestingly, we found that neutralization of TIMP-1 with antibody or knockdown with siRNA in astrocytes abolished most of the neuroprotective ability of the 6h Aβ-ACM onAβ-treated cultured neurons. Furthermore addition of exogenous rat recombinant TIMP-1 protein protects primary neurons from Aβ mediated toxicity. In a well characterized Aβ-infused rodent model of AD, intra-cerebroventricular administration of TIMP-1 revealed a reduction inAβ load and apoptosis in hippocampal and cortical regions. Finally, we found that TIMP-1 can ameliorate Aβ-induced cognitive dysfunctions through restoration of Akt and its downstream pathway and maintenance of synaptic integrity. Thus, our results not only provide a functional clarity for TIMP-1,secreted by activated astrocytes, but also support it as a major candidate in cytokine-mediated therapy of AD especially at the early phase of disease progression.

中文翻译：

TIMP-1：活化星形胶质细胞释放的一种关键细胞因子保护神经元并改善阿尔茨海默病啮齿动物模型的认知行为

阿尔茨海默病 (AD) 的特征在于两种病理类型，即细胞外淀粉样蛋白-β (Aβ) 斑块和细胞内神经原纤维缠结。在包括 AD 在内的各种神经系统疾病中，维持大脑正常稳态的星形胶质细胞会经历一系列称为反应性星形胶质细胞增生的分子、细胞和功能变化。据推测，反应性星形胶质细胞最初倾向于通过减少 Aβ 负荷和分泌过多的细胞因子来保护神经元，然而，它们的功能研究很少。我们对 Aβ 暴露后皮质星形胶质细胞活化动力学的研究揭示了早在 6 小时内就有显着的活化水平。来自 6 小时 Aβ 处理的星形胶质细胞 (Aβ-ACM) 的星形胶质细胞条件培养基 (ACM) 为培养的皮层神经元提供了针对 Aβ 损伤的显着神经保护作用。对 Aβ-ACM 中分泌蛋白的分析显示，金属蛋白酶-1 (TIMP-1) 的组织抑制剂在 6 小时内显着增加。有趣的是，我们发现在星形胶质细胞中用抗体中和 TIMP-1 或用 siRNA 敲低消除了 6 小时 Aβ-ACM 对 Aβ 处理的培养神经元的大部分神经保护能力。此外，外源性大鼠重组 TIMP-1 蛋白的添加保护原代神经元免受 Aβ 介导的毒性。在一个充分表征的 Aβ 注入的 AD 啮齿动物模型中，脑室内施用 TIMP-1 显示海马和皮质区域的 Aβ 负荷和细胞凋亡减少。最后，我们发现 TIMP-1 可以通过恢复 Akt 及其下游通路和维持突触完整性来改善 Aβ 诱导的认知功能障碍。因此，

更新日期：2020-07-01

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