Chen Jiacheng, Guo Ning, Ruan Yuting, Mai Yingren, Liao Wang, Feng Yanqing
Department of Neurology, National Key Clinical Department, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, China.
Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Front Aging Neurosci. 2023 Jan 19;15:1105095. doi: 10.3389/fnagi.2023.1105095. eCollection 2023.
Alzheimer's disease (AD) is characterized by amyloid β (Aβ) aggregation and neuroinflammation. This study aimed to investigate the therapeutic effect of isoniazid (INH) against AD.
The APP/PS1 transgenic mouse model of AD was adopted. The APP/PS1 mice received oral INH (45 mg/kg/d) for 14 days. The cognitive capability was assessed by the Morris Water Maze test. Amyloid plaques and Aβ levels were determined by immunohistochemistry and ELISA assay. The dendritic spines were analyzed by DiOlistic labeling. Immunofluorescence staining was used to observe the microglia and astrocytes.
The Morris Water Maze test suggested that INH administration can effectively attenuate the reference memory deficit and improve the working memory of the APP/PS1 mice compared to the untreated mice (all < 0.001). INH significantly decreased the Aβ plaques in the hippocampus and cortex and reduced the levels of Aβ and Aβ in the brain homogenates, cerebrospinal fluid, and serum (all < 0.001). INH also inhibited enzyme activities of β-site amyloid precursor protein cleaving enzyme 1 (BACE1, < 0.05) and monoamine oxidase B (Mao-b, < 0.01). INH significantly increased the protrusion density in the hippocampus ( < 0.01). Immunofluorescence staining revealed that INH significantly reduced the number of activated microglia and astrocytes around the Aβ plaques (both < 0.01).
Isoniazid administration effectively improved cognitive performance, cleared Aβ plaques, protected dendritic synapses, and reduced innate immune cells around the Aβ plaques, suggesting that INH could be a potential drug for AD treatment.
阿尔茨海默病（AD）的特征是淀粉样蛋白β（Aβ）聚集和神经炎症。本研究旨在探讨异烟肼（INH）对AD的治疗作用。
采用AD的APP/PS1转基因小鼠模型。APP/PS1小鼠口服INH（45毫克/千克/天），持续14天。通过莫里斯水迷宫试验评估认知能力。通过免疫组织化学和ELISA测定法测定淀粉样斑块和Aβ水平。通过微粒轰击标记分析树突棘。采用免疫荧光染色观察小胶质细胞和星形胶质细胞。
莫里斯水迷宫试验表明，与未治疗的小鼠相比，给予INH可有效减轻APP/PS1小鼠的参考记忆缺陷并改善其工作记忆（均P<0.001）。INH显著减少海马体和皮质中的Aβ斑块，并降低脑匀浆、脑脊液和血清中Aβ和Aβ的水平（均P<0.001）。INH还抑制β位点淀粉样前体蛋白裂解酶1（BACE1，P<0.05）和单胺氧化酶B（Mao-b，P<0.01）的酶活性。INH显著增加海马体中的突起密度（P<0.01）。免疫荧光染色显示，INH显著减少Aβ斑块周围活化的小胶质细胞和星形胶质细胞的数量（均P<0.01）。
给予异烟肼可有效改善认知表现、清除Aβ斑块、保护树突突触并减少Aβ斑块周围的固有免疫细胞，表明INH可能是一种治疗AD的潜在药物。
