AngIV-Analog Dihexa 通过 PI3K/AKT 信号通路在 APP/PS1 鼠标中拯救认知障碍并恢复记忆,Brain Sciences

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AngIV-Analog Dihexa 通过 PI3K/AKT 信号通路在 APP/PS1 鼠标中拯救认知障碍并恢复记忆
Brain Sciences ( IF 2.7 ) Pub Date : 2021-11-11 , DOI: 10.3390/brainsci11111487
Xiaojin Sun ₁ , Yang Deng ₁ , Xinxin Fu ₁ , Siyu Wang ₂ , Rui Duan ₂ , Yingdong Zhang ₁

Affiliation

肾素-血管紧张素系统 (RAS) 是中枢神经系统 (CNS) 内的旁分泌 RAS，与阿尔茨海默病 (AD) 密切相关。内源性六肽血管紧张素 IV (Ang IV) 是大脑 RAS 的重要组成部分，在先前的研究中被发现可以挽救认知障碍并恢复记忆力。在我们的研究中，我们使用了不同剂量的 Dihexa，可以口服给药并穿过 APP/PS1 小鼠的 BBB。我们发现与 WT 组相比，给予 Dihexa 后小鼠组织中 AngIV 的量增加。同时，Dihexa 在莫里斯水迷宫测试中恢复了空间学习和认知功能。在 Nissl 染色中，Dihexa 增加了 APP/PS1 小鼠中神经元细胞和 SYP 蛋白的表达。此外，Dihexa 降低了星形胶质细胞和小胶质细胞的活化，显着降低促炎细胞因子 IL-1β 和 TNF-α 的水平，并增加抗炎细胞因子 IL-10 的水平。Dihexa 激活了 PI3K/AKT 信号通路，而 PI3K 抑制剂渥曼青霉素显着逆转了 APP/PS1 小鼠的抗炎和抗凋亡作用。这些发现突出了脑 AngIV/PI3K/AKT 轴作为治疗 AD 的潜在靶点。

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AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway

The renin-angiotensin system (RAS) is a paracrine RAS within the central nervous system (CNS) and is closely related to Alzheimer’s disease (AD). The endogenous hexapeptide angiotensin IV (Ang IV), an important component of the brain RAS, was found to rescue cognitive impairment and recover memory in previous studies. In our study, we used different doses of Dihexa, which can be orally administered and cross the BBB in APP/PS1 mice. We found that the amount of AngIV in mouse tissue increased after the administration of Dihexa compared to that in the WT group. Meanwhile, Dihexa restored spatial learning and cognitive functions in the Morris water maze test. Dihexa increased the neuronal cells and the expression of SYP protein in APP/PS1 mice in Nissl staining. Furthermore, Dihexa decreased the activation of astrocytes and microglia, markedly reduced levels of the pro-inflammatory cytokines IL-1β and TNF-α and increased the levels of the anti-inflammatory cytokine IL-10. Dihexa activated the PI3K/AKT signaling pathway, while PI3K inhibitor wortmannin significantly reversed the anti-inflammatory and anti-apoptotic effects of APP/PS1 mice. These findings highlight the brain AngIV/PI3K/AKT axis as a potential target for the treatment of AD.

更新日期：2021-11-11

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