NEURON
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2022
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IF 18.688
Jin Hu,Qiang Chen,Hongrui Zhu,Lichao Hou,Wei Liu,Qihua Yang,Huidan Shen,Guolin Chai,Boxin Zhang,Shaoxuan Chen,Zhiyu Cai,Chongxin Wu,Fan Hong,Hongda Li,Sifang Chen,Naian Xiao,Zhan-xiang Wang,Xueqin Zhang,Bo Wang,Liang Zhang,Wei Mo
Summary The pathology of Alzheimer’s disease (AD) is featured with extracellular amyloid-β (Aβ) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced Ca 2+ influx for microglial clustering, phagocytosis , and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD.
研究领域:
神经科学
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病理学
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细胞生物学
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DOI
PubMed
高影响因子
Advanced Science
·
2023
·Vol. 10
·期 18
·2301361
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IF 15.1
Yanrong Su,Yufen Huang,Qinjie Kou,Lu Lu,Haiye Jiang,Xisheng Li,Rong Gui,Rong Huang,Xueyuan Huang,Jinqi Ma,Jian Li,Xinmin Nie
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the elderly population. Despite significant advances in studies of the pathobiology on AD, there is still no effective treatment. Here, an erythrocyte membrane-camouflaged nanodrug delivery system (TR-ZRA) modified with transferrin receptor aptamers that can be targeted across the blood–brain barrier to ameliorate AD immune environment is established. Based on metal-organic framework (Zn-CA), TR-ZRA is loaded with CD22shRNA plasmid to silence the abnormally high expression molecule CD22 in aging microglia. Most importantly, TR-ZRA can enhance the ability of microglia to phagocytose A β and alleviate complement activation, which can promote neuronal activity and decrease inflammation level in the AD brain. Moreover, TR-ZRA is also loaded with A β aptamers, which allow rapid and low-cost monitoring of A β plaques in vitro. After treatment with TR-ZRA, learning, and memory abilities are enhanced in AD mice. In conclusion, the biomimetic delivery nanosystem TR-ZRA in this study provides a promising strategy and novel immune targets for AD therapy.
研究领域:
神经科学
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药学
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纳米技术
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免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Hui-Han Ma,Jia-Yi Zheng,Yu-Hui Qiu,Shan Su,Fang-Mei Lu,Guang-Liang Wu,Shi-Jie Zhang,Ye-Feng Cai
Ethnopharmacological relevance Alzheimer's disease (AD) is a common type of neurodegenerative disease with the β-amyloid plaques (Aβ) deposition. Previously, Dengzhan Shengmai capsule (DZSM) has been shown to reduce the pathology associated with AD, but the underlying mechanism is unclear. Aim of study This study investigated the potential mechanisms of DZSM against AD. Materials and methods The six-month-old wild-type male mice and APP/PS1 double transgenic male mice were administered 0.9 % saline or DZSM for 8 weeks by gavage. Open field test, new object recognition test, and Morris Water maze test were used to assess spatial learning and memory. Aβ plaques in brains were visualized using ThT staining. Nissl staining, TUNEL staining, and Western blot analyses were used to detect the neuronal function and apoptosis level. The superoxide dismutase (SOD), glutathione peroxidase assay kit (GSH-Px), and malondialdehyde (MDA) kits were performed to assess oxidative stress levels. Then, immunofluorescence and Western blot analysis were applied to evaluate ER stress pathway protein levels. Finally, HT22 cells were treated by Aβ 1-42 with or without DZSM medicated serum. Cell viability was assessed using the CCK-8 assay, and Western blot analysis was applied to evaluate ER stress pathway protein levels. Results Open filed test, new object recognition test and Morris Water maze test showed that DZSM restored cognitive disorders in APP/PS1 mice. Immunohistochemistry and Thioflavin T staining results indicated that DZSM reduced Aβ plaques in the brain. Deeper and denser Nissl bodies were found in APP/PS1 mice after DZSM administration. Besides, APP/PS1 mice treated with DZSM showed a lower level of TUNEL and Bax/Bcl-2 ratio. DZSM improved the acetylcholine (ACh), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity while reducing acetylcholinesterase (AChE) and malondialdehyde (MDA) activity. In addition, the levels of ER stress pathway containing Phospho-PKR-like ER kinase (P-PERK), phosphorylate eukaryotic initiation factor 2 (P-eIF2α), activating transcription factor 4 (ATF4), glutamine-rich protein 1 (QRICH1), phosphorylate inositol-requiring protein 1α (P-IRE1α), the spliced form of X-box binding protein 1 (XBP1s), activating transcription factor-6 (ATF6) and C/EBP homologous binding protein (CHOP) were decreased by DZSM. CCK-8 results indicated that DZSM medicated serum played cytoprotective effects on Aβ 1-42 -induced HT22 cells. Western blot results suggested DZSM possibly inhibited ER stress pathways in Aβ 1-42 -induced HT22 cells. Conclusion The potential protective mechanism of DZSM on cognitive impairment in AD might be related to ER stress pathways.
研究领域:
神经药理学
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民族药理学
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神经退行性疾病
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
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2024
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IF 4
Song Zhenyan,He Jiawei,Yu Wenjing,He Chunxiang,Yang Miao,Li Ping,Li Ze,Jian Gonghui,Cheng Shaowu
Background: Schisanlactone E, also known as XueTongSu (XTS), is an active compound extracted from the traditional Tujia medicine Kadsura heteroclita (“XueTong”). Recent studies highlight its anti-inflammatory and antioxidant properties, yet the mechanisms of XTS’s therapeutic effects on Alzheimer’s disease (AD) are unclear. This study aims to elucidate the therapeutic efficacy and mechanisms of XTS in AD.Methods: Ten C57BL/6 mice were assigned to the control group (NC), and twenty APP/PS1 transgenic mice were randomly divided into the model group (M) (10 mice) and the XTS treatment group (Tre) (10 mice). After an acclimatization period of 7 days, intraperitoneal injections were administered over a 60-day treatment period. The NC and M groups received saline, while the Tre group received XTS at 2 mg/kg. Learning and memory abilities were assessed using the Morris Water Maze (MWM) test. Histopathological changes were evaluated using hematoxylin and eosin (HE) and Nissl staining, and immunofluorescence was used to assess pathological products and glial cell activation. Cytokine levels (IL-1β, IL-6, TNF-α) in the hippocampus were quantified by qPCR. 16S rDNA sequencing analyzed gut microbiota metabolic alterations, and metabolomic analysis was performed on cortical samples. The KEGG database was used to analyze the regulatory mechanisms of XTS in AD treatment.Results: XTS significantly improved learning and spatial memory in APP/PS1 mice and ameliorated histopathological changes, reducing Aβ plaque aggregation and glial cell activation. XTS decreased the expression of inflammatory cytokines IL-1β, IL-6, and TNF-α. It also enhanced gut microbiota diversity, notably increasing Akkermansia species, and modulated levels of metabolites such as isosakuranetin, 5-KETE, 4-methylcatechol, and sphinganine. Pathway analysis indicated that XTS regulated carbohydrate metabolism, neuroactive ligand-receptor interactions, and alanine, aspartate, and glutamate metabolism, mitigating gut microbiota dysbiosis and metabolic disturbances.Conclusion: XTS ameliorates cognitive deficits, pathological changes, and inflammatory responses in APP/PS1 mice. It significantly modulates the gut microbiota, particularly increasing Akkermansia abundance, and influences levels of key metabolites in both the gut and brain. These findings suggest that XTS exerts anti-AD effects through the microbial-gut-brain axis (MGBA).
研究领域:
神经科学
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药理学
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分子生物学
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微生物学
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代谢组学
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DOI
高影响因子
危险品化学品经营许可证（带存储）