一种 GLP-1/GIP 双重受体激动剂 DA4-JC 可有效减轻阿尔茨海默病 APP/PS1/Tau 模型的认知障碍和病理。

A GLP-1/GIP Dual Receptor Agonist DA4-JC Effectively Attenuates Cognitive Impairment and Pathology in the APP/PS1/Tau Model of Alzheimer's Disease.

机构信息

Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China.

Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China.

出版信息

J Alzheimers Dis. 2021;83(2):799-818. doi: 10.3233/JAD-210256.

DOI:10.3233/JAD-210256

PMID:34366339

Abstract

BACKGROUND

Alzheimer's disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs.

OBJECTIVE

To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD.

METHODS

A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers.

RESULTS

DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels.

CONCLUSION

DA4-JC is a promising drug for the treatment of AD.

摘要

背景

阿尔茨海默病（AD）是一种进行性神经退行性疾病，伴有进行性认知能力下降，目前尚无治愈方法。最近，AD 与 2 型糖尿病（T2DM）之间的密切相关性已被注意到，一种有前途的抗 AD 策略是使用抗 T2DM 药物。

目的

研究新型胰高血糖素样肽-1（GLP-1）/葡萄糖依赖性胰岛素释放肽（GIP）受体激动剂 DA4-JC 是否对 AD 的三转基因 APP/PS1/tau 小鼠模型具有保护作用。

方法

一系列行为测试后，通过在体记录海马长时程增强（LTP），使用高尔基法对突触进行定量分析，并进行生物化学分析生物标志物。

结果

DA4-JC 改善了 APP/PS1/tau 小鼠的认知障碍，减轻了其病理特征，增强了海马中的 LTP，增加了突触和树突棘的数量，上调了突触后密度蛋白 95（PSD95）和突触小体蛋白（SYP）的水平，使磷酸酶和张力蛋白同源物诱导的潜在激酶 1（PINK1）-Parkin 线粒体自噬信号通路正常化，同时降低了淀粉样蛋白、p-tau 和自噬标志物 P62 的水平。