Calpeptin improves the cognitive function in Alzheimer's disease-like complications of diabetes mellitus rats by regulating TXNIP/NLRP3 inflammasome

IF 3.1 3区医学 Q2 ENDOCRINOLOGY & METABOLISM Journal of Diabetes Investigation Pub Date : 2024-08-22 DOI:10.1111/jdi.14292

Luyao Qiao, Shouqin Yi, Tianpei Li, Xin Pan, Gege Wang, Xu Liu, Min Li, Jun Min, Huahui Le, Zhenyu Tang

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Abstract

Aims

Diabetes mellitus (DM) is closely associated with Alzheimer's disease (AD), and is considered an accelerator of AD. Our previous study has confirmed that the Calpain inhibitor Calpeptin may alleviate AD-like complications of diabetes mellitus. This work further investigated its underlying mechanism.

Materials and Methods

Diabetes mellitus rat model was constructed by a high-fat and high-sugar diet combined with streptozotocin, followed by the administration of Calpeptin. Moreover, rats were micro-injected with LV-TXNIP-OE/vector into the CA1 region of the hippocampus one day before streptozotocin injection. The Morris water maze test assessed the spatial learning and memory ability of rats. Immunohistochemistry and western blotting detected the expression of the pericyte marker PDGFRβ, tight junction proteins occludin and ZO-1, calpain-1, calpain-2, APP, Aβ, Aβ-related, and TXNIP/NLRP3 inflammasome-related proteins. Immunofluorescence staining examined the blood vessel density and neurons in the hippocampus. Evans blue extravasation and fluorescence detected the permeability of the blood–brain barrier (BBB) in rats. Additionally, the oxidative stress markers and inflammatory-related factors were assessed by enzyme-linked immunosorbent assay.

Results

Calpeptin effectively reduced the expression of Calpain-2 and TXNIP/NLRP3 inflammasome-related proteins, improved the decreased pericyte marker (PDGFR-β) and cognitive impairment in hippocampus of DM rats. The neuronal loss, microvessel density, permeability of BBB, Aβ accumulation, inflammation, and oxidative stress injury in the hippocampus of DM rats were also partly rescued by calpeptin treatment. The influence conferred by calpeptin treatment was reversed by TXNIP overexpression.

Conclusions

These data demonstrated that calpeptin treatment alleviated AD-like symptoms in DM rats through regulating TXNIP/NLRP3 inflammasome. Thus, calpeptin may be a potential drug to treat AD-like complications of diabetes mellitus.

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钙蛋白通过调节TXNIP/NLRP3炎性体改善糖尿病大鼠阿尔茨海默病样并发症的认知功能

目的：糖尿病（DM）与阿尔茨海默病（AD）密切相关，被认为是阿尔茨海默病的加速器。我们之前的研究证实，钙蛋白酶抑制剂钙蛋白酶可减轻糖尿病类似于阿尔茨海默病的并发症。本研究进一步探讨了其潜在机制：通过高脂高糖饮食结合链脲佐菌素构建糖尿病大鼠模型，然后给予钙蛋白酶。此外，大鼠在注射链脲佐菌素前一天在海马 CA1 区微量注射 LV-TXNIP-OE/载体。莫里斯水迷宫测试评估了大鼠的空间学习和记忆能力。免疫组化和Western印迹检测了周细胞标志物PDGFRβ、紧密连接蛋白闭塞素和ZO-1、钙蛋白酶-1、钙蛋白酶-2、APP、Aβ、Aβ相关蛋白和TXNIP/NLRP3炎性体相关蛋白的表达。免疫荧光染色检查了海马的血管密度和神经元。伊文思蓝外渗和荧光检测了大鼠血脑屏障（BBB）的通透性。此外，还通过酶联免疫吸附试验评估了氧化应激标志物和炎症相关因子：结果：钙蛋白能有效降低钙蛋白酶-2和TXNIP/NLRP3炎症体相关蛋白的表达，改善DM大鼠海马周细胞标志物（PDGFR-β）的减少和认知功能障碍。钙调蛋白还能部分缓解DM大鼠海马的神经元丢失、微血管密度、BBB通透性、Aβ积累、炎症和氧化应激损伤。TXNIP的过表达逆转了钙蛋白治疗的影响：这些数据表明，钙蛋白肽治疗可通过调节TXNIP/NLRP3炎性体缓解DM大鼠的AD样症状。因此，钙蛋白可能是治疗糖尿病AD样并发症的潜在药物。

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来源期刊

Journal of Diabetes Investigation ENDOCRINOLOGY & METABOLISM-

CiteScore

6.50

自引率

9.40%

发文量

218

审稿时长

6-12 weeks

期刊介绍： Journal of Diabetes Investigation is your core diabetes journal from Asia; the official journal of the Asian Association for the Study of Diabetes (AASD). The journal publishes original research, country reports, commentaries, reviews, mini-reviews, case reports, letters, as well as editorials and news. Embracing clinical and experimental research in diabetes and related areas, the Journal of Diabetes Investigation includes aspects of prevention, treatment, as well as molecular aspects and pathophysiology. Translational research focused on the exchange of ideas between clinicians and researchers is also welcome. Journal of Diabetes Investigation is indexed by Science Citation Index Expanded (SCIE).