{"title":"化合物(E)-2-(3,4-二羟基苯乙烯基)-3-羟基-4H-吡喃-4-酮下调Galectin-3可改善5×FAD小鼠Aβ发病机制诱发的神经炎症。","authors":"","doi":"10.1016/j.lfs.2024.123085","DOIUrl":null,"url":null,"abstract":"<div><h3>Aims</h3><div>Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aβ pathogenesis. However, strategies to simultaneously target Gal-3 and Aβ are currently insufficient. This study evaluates the therapeutic efficacy of (<em>E</em>)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), in reducing Gal-3 and Aβ pathogenesis.</div></div><div><h3>Materials and methods</h3><div>We applied exogenous oligomeric Aβ and used 5 × FAD mice to assess the impact of Aβ on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST).</div></div><div><h3>Key findings</h3><div>D30 effectively reduced Aβ monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aβ aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST.</div></div><div><h3>Significance</h3><div>Our findings underscore the interaction between Gal-3 and Aβ in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aβ is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one downregulation of Galectin-3 ameliorates Aβ pathogenesis-induced neuroinflammation in 5 × FAD mice\",\"authors\":\"\",\"doi\":\"10.1016/j.lfs.2024.123085\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Aims</h3><div>Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aβ pathogenesis. However, strategies to simultaneously target Gal-3 and Aβ are currently insufficient. This study evaluates the therapeutic efficacy of (<em>E</em>)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), in reducing Gal-3 and Aβ pathogenesis.</div></div><div><h3>Materials and methods</h3><div>We applied exogenous oligomeric Aβ and used 5 × FAD mice to assess the impact of Aβ on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST).</div></div><div><h3>Key findings</h3><div>D30 effectively reduced Aβ monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aβ aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST.</div></div><div><h3>Significance</h3><div>Our findings underscore the interaction between Gal-3 and Aβ in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aβ is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.</div></div>\",\"PeriodicalId\":18122,\"journal\":{\"name\":\"Life sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Life sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0024320524006751\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0024320524006751","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one downregulation of Galectin-3 ameliorates Aβ pathogenesis-induced neuroinflammation in 5 × FAD mice
Aims
Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aβ pathogenesis. However, strategies to simultaneously target Gal-3 and Aβ are currently insufficient. This study evaluates the therapeutic efficacy of (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), in reducing Gal-3 and Aβ pathogenesis.
Materials and methods
We applied exogenous oligomeric Aβ and used 5 × FAD mice to assess the impact of Aβ on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST).
Key findings
D30 effectively reduced Aβ monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aβ aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST.
Significance
Our findings underscore the interaction between Gal-3 and Aβ in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aβ is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.
期刊介绍:
Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed.
The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.