Zhang Limin, An Hongmei, Zhen Rongrong, Zhang Tong, Ding Minrui, Zhang Mengxue, Sun Yiguo, Gu Chao
Department of Neurology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Science & Technology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Alzheimers Dis. 2025 Jan;103(2):372-382. doi: 10.1177/13872877241299832. Epub 2025 Jan 28.
Alzheimer's disease (AD) is an irreversible age-related neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Di Huang Yi Zhi (DHYZ) formula, a traditional Chinese herbal compound comprising several prescriptions, demonstrates properties that improve cognitive abilities in clinical. Nonetheless, its molecular mechanisms on treating AD through improving neuron cells mitochondria function have not been deeply investigated.
This study administered DHYZ to APP/PS1 mice to explore its potential therapeutic mechanisms in AD treatment.
APP/PS1 transgenic mice were given DHYZ (L, M, H), donepezil, or distilled water for a consecutive 12-week period. The Morris water maze test was used to assess memory capacity, transmission electron microscopy was used to observe mitochondrial and synaptic structures, immunohistochemistry and western blot detected proteins involved in the mitochondrial autophagy pathway, ELISA measured serum Aβ content, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assessed neuronal cell apoptosis.
DHYZ demonstrates a notable therapeutic impact on mice with AD, effectively improving cognitive and memory impairments. DHYZ decreases Aβ accumulation in the hippocampus by reducing BACE1 activity and enhancing Aβ clearance through the blood-brain barrier. Additionally, DHYZ significantly suppresses neuronal apoptosis, enhances synaptic structure, and increases synapse numbers, processes strongly linked to the activation of mitochondrial PINK1-Parkin autophagy.
DHYZ enhances cognitive function in APP/PS1 mice by stimulating neuronal mitochondrial autophagy through the PINK1-Parkin pathway.
阿尔茨海默病（AD）是一种与年龄相关的不可逆神经退行性疾病，其特征是β-淀粉样蛋白（Aβ）肽沉积和神经原纤维缠结。地黄益智（DHYZ）方是一种由多个方剂组成的传统中药复方，在临床上具有改善认知能力的特性。然而，其通过改善神经元细胞线粒体功能治疗AD的分子机制尚未得到深入研究。
本研究对APP/PS1小鼠给予DHYZ，以探索其在AD治疗中的潜在治疗机制。
对APP/PS1转基因小鼠连续12周给予DHYZ（低、中、高剂量）、多奈哌齐或蒸馏水。采用莫里斯水迷宫试验评估记忆能力，透射电子显微镜观察线粒体和突触结构，免疫组织化学和蛋白质免疫印迹法检测线粒体自噬途径相关蛋白，酶联免疫吸附测定法测量血清Aβ含量，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法评估神经元细胞凋亡。
DHYZ对AD小鼠具有显著的治疗作用，有效改善认知和记忆障碍。DHYZ通过降低β-分泌酶1（BACE1）活性和增强Aβ通过血脑屏障的清除来减少海马中Aβ的积累。此外，DHYZ显著抑制神经元凋亡，增强突触结构，并增加突触数量，这些过程与线粒体PINK1-Parkin自噬的激活密切相关。
DHYZ通过PINK1-Parkin途径刺激神经元线粒体自噬，增强APP/PS1小鼠的认知功能。
