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Outline
Alzheimer's disease (AD) is a chronic neurodegenerative disorder. Current medications can only alleviate symptoms but have not yet achieved a cure. Given its multifactorial pathogenesis, the development of small-molecule compounds that act simultaneously on multiple targets is particularly important. Traditional Chinese medicine (TCM) small molecules, which can regulate multiple biological targets and signaling pathways, offer unique advantages in AD treatment. This study utilized genipin, a TCM small molecule with potential neuroprotective effects, as the lead compound to design and synthesize a series of multi-target anti-AD small molecule compounds. Among these, compounds JD-5 and JD-7 exhibited significantly enhanced GSK-3β inhibitory activity (JD-5, IC50 = 3.54 μmol·L-1; JD-7, IC50 = 2.47 μmol·L-1), substantially outperforming the lead compound genipin (IC50 = 28.16 μmol·L-1). Furthermore, both JD-5 and JD-7 demonstrated significant neuroprotective effects in SH-SY5Y cell damage experiments induced by tBHP and Aβ25-35. Further investigation revealed that compounds JD-5 and JD-7 could significantly reduce Tau phosphorylation (S396) levels in primary neuronal cells, with dose-dependent effects. All animal experiments were approved by the Experimental Animal Ethics Committee of Nanjing Ramda Pharmaceutical Co., Ltd (approval number: IACUC-20220202). Based on these results, it is hypothesized that compound JD-5 likely exerts neuroprotective and antioxidant stress effects by inhibiting GSK-3β activity and reducing Tau protein phosphorylation levels, providing a reference for the development of multifunctional anti-AD drugs.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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