Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Huang-Lian-Jie-Du Decoction alleviates cognitive deficits in Alzheimer's disease via aromatase-mediated regulation of Aβ metabolism.
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Sun Mingguang, Ye Dongsheng, Min Puxuan, Guo Mengxiong, Zhao Xiao, Zhou Yue, Xu Lingxu, Wu Yutong, Meng Zhaoyou, Wang Gesheng
Аннотация
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological accumulation of amyloid-β (Aβ). Hippocampal aromatase (AROM), a key enzyme for local estrogen biosynthesis, has emerged as an important regulator of Aβ metabolism. Huang-Lian-Jie-Du Decoction (HLJD), a classical traditional Chinese medicine formula, has shown therapeutic potential in AD; however, its molecular mechanism remains largely unclear.
METHODS: The effects of HLJD on cognitive function and Aβ metabolism were evaluated in APP/PS1 transgenic mice and Aβ1-42-induced HT22 cells. Behavioral performance was assessed using the Morris water maze. Aβ burden and the expression of Aβ-related metabolic enzymes (BACE1, IDE, and NEP) were analyzed by western blotting, qRT-PCR, and immunofluorescence. Network pharmacology was applied to predict potential targets and pathways of HLJD. Gain and loss of function experiments targeting AROM were performed to determine its mechanistic involvement.
RESULTS: HLJD significantly improved learning and memory deficits and reduced hippocampal Aβ accumulation in APP/PS1 mice without altering APP expression. In both in vivo and in vitro models, HLJD significantly upregulated AROM expression. HLJD suppressed Aβ production by downregulating BACE1 while enhancing Aβ degradation through upregulation of IDE and NEP. Importantly, AROM knockdown largely abolished the regulatory effects of HLJD on Aβ metabolism, whereas AROM overexpression reproduced its protective actions.
CONCLUSION: These findings demonstrate that HLJD alleviates cognitive impairment in AD models by activating hippocampal aromatase and restoring Aβ homeostasis through coordinated regulation of Aβ production and degradation. This study identifies AROM as a critical mediator of HLJD's neuroprotective effects and highlights AROM-dependent modulation of local estrogen synthesis as a promising therapeutic strategy for Alzheimer's disease.
METHODS: The effects of HLJD on cognitive function and Aβ metabolism were evaluated in APP/PS1 transgenic mice and Aβ1-42-induced HT22 cells. Behavioral performance was assessed using the Morris water maze. Aβ burden and the expression of Aβ-related metabolic enzymes (BACE1, IDE, and NEP) were analyzed by western blotting, qRT-PCR, and immunofluorescence. Network pharmacology was applied to predict potential targets and pathways of HLJD. Gain and loss of function experiments targeting AROM were performed to determine its mechanistic involvement.
RESULTS: HLJD significantly improved learning and memory deficits and reduced hippocampal Aβ accumulation in APP/PS1 mice without altering APP expression. In both in vivo and in vitro models, HLJD significantly upregulated AROM expression. HLJD suppressed Aβ production by downregulating BACE1 while enhancing Aβ degradation through upregulation of IDE and NEP. Importantly, AROM knockdown largely abolished the regulatory effects of HLJD on Aβ metabolism, whereas AROM overexpression reproduced its protective actions.
CONCLUSION: These findings demonstrate that HLJD alleviates cognitive impairment in AD models by activating hippocampal aromatase and restoring Aβ homeostasis through coordinated regulation of Aβ production and degradation. This study identifies AROM as a critical mediator of HLJD's neuroprotective effects and highlights AROM-dependent modulation of local estrogen synthesis as a promising therapeutic strategy for Alzheimer's disease.