Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer’s disease by regulating microglia homeostasis and inhibiting HMGB1 pathway
Abstract Background Recent studies suggest that opioid receptor signaling may differentially affect Alzheimer’s disease (AD) pathology and the relevant behavioral dysfunctions. However, the precise roles and mechanisms of opioid receptor subtypes in AD pathologies are still unclear with major contro...
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BMC
2025-02-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01682-1 |
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| author | Yuan Xu Naiyuan Shao Feng Zhi Ronghua Chen Yilin Yang Jiahui Li Ying Xia Ya Peng |
| author_facet | Yuan Xu Naiyuan Shao Feng Zhi Ronghua Chen Yilin Yang Jiahui Li Ying Xia Ya Peng |
| author_sort | Yuan Xu |
| collection | DOAJ |
| description | Abstract Background Recent studies suggest that opioid receptor signaling may differentially affect Alzheimer’s disease (AD) pathology and the relevant behavioral dysfunctions. However, the precise roles and mechanisms of opioid receptor subtypes in AD pathologies are still unclear with major controversies. Methods We compared the delta-opioid receptor (DOR)- and mu-opioid receptor (MOR)-mediated effects on AD-associated cognitive deficits, pathologies, neuroinflammations, cell death using transgenic APP/PS1 mouse model and BV2 cell line at behavioral, molecular, and cellular levels. Unpaired t-test and one/two way analysis for variance (ANOVA) were used to analyze statistical significance of the data. Results We show a distinct role of DOR and its major difference with MOR in AD injury in an APP/PS1 mouse model. DOR activation by UFP-512, but not MOR activation by DAMGO, attenuated cognitive impairment, reduced beta-amyloid (Aβ) production and aggregation, as well as protected the neurons from apoptosis in APP/PS1 mice. DOR and MOR also differentially modulated microglia in APP/PS1 mice and in vitro AD cell model with a DOR-mediated inhibition on the excessive activation of microglia and the release of pro-inflammatory cytokines in AD pathologies. Gene expression profiling further revealed that the alternations in DOR/MOR are closely associated with microglial homeostatic signatures and high mobility group protein B1 (HMGB1) in AD. DOR activation inhibited HMGB1 secretion and its translocation from nuclear to cytoplasm. Our in-vitro studies further confirmed that DOR overexpression mitigated microglial inflammatory response and rescued neurons from AD injury via HMGB1-NF-κB signaling pathway. Conclusions These novel findings uncover previously unappreciated roles of DOR in neuroprotection against AD injury via modulating microglia-related inflammatory responses. |
| format | Article |
| id | doaj-art-e023028a1369464999b4bf019bc68592 |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-e023028a1369464999b4bf019bc685922025-02-02T12:11:53ZengBMCAlzheimer’s Research & Therapy1758-91932025-02-0117112310.1186/s13195-025-01682-1Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer’s disease by regulating microglia homeostasis and inhibiting HMGB1 pathwayYuan Xu0Naiyuan Shao1Feng Zhi2Ronghua Chen3Yilin Yang4Jiahui Li5Ying Xia6Ya Peng7Department of Neurosurgery, The First People’s Hospital of ChangzhouDepartment of Neurosurgery, The First People’s Hospital of ChangzhouDepartment of Neurosurgery, The First People’s Hospital of ChangzhouDepartment of Neurosurgery, The First People’s Hospital of ChangzhouDepartment of Neurosurgery, The First People’s Hospital of ChangzhouShanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan UniversityShanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan UniversityDepartment of Neurosurgery, The First People’s Hospital of ChangzhouAbstract Background Recent studies suggest that opioid receptor signaling may differentially affect Alzheimer’s disease (AD) pathology and the relevant behavioral dysfunctions. However, the precise roles and mechanisms of opioid receptor subtypes in AD pathologies are still unclear with major controversies. Methods We compared the delta-opioid receptor (DOR)- and mu-opioid receptor (MOR)-mediated effects on AD-associated cognitive deficits, pathologies, neuroinflammations, cell death using transgenic APP/PS1 mouse model and BV2 cell line at behavioral, molecular, and cellular levels. Unpaired t-test and one/two way analysis for variance (ANOVA) were used to analyze statistical significance of the data. Results We show a distinct role of DOR and its major difference with MOR in AD injury in an APP/PS1 mouse model. DOR activation by UFP-512, but not MOR activation by DAMGO, attenuated cognitive impairment, reduced beta-amyloid (Aβ) production and aggregation, as well as protected the neurons from apoptosis in APP/PS1 mice. DOR and MOR also differentially modulated microglia in APP/PS1 mice and in vitro AD cell model with a DOR-mediated inhibition on the excessive activation of microglia and the release of pro-inflammatory cytokines in AD pathologies. Gene expression profiling further revealed that the alternations in DOR/MOR are closely associated with microglial homeostatic signatures and high mobility group protein B1 (HMGB1) in AD. DOR activation inhibited HMGB1 secretion and its translocation from nuclear to cytoplasm. Our in-vitro studies further confirmed that DOR overexpression mitigated microglial inflammatory response and rescued neurons from AD injury via HMGB1-NF-κB signaling pathway. Conclusions These novel findings uncover previously unappreciated roles of DOR in neuroprotection against AD injury via modulating microglia-related inflammatory responses.https://doi.org/10.1186/s13195-025-01682-1Alzheimer’s diseaseCognitive impairmentβ-amyloidNeuroinflammationDelta-opioid receptorMicroglia |
| spellingShingle | Yuan Xu Naiyuan Shao Feng Zhi Ronghua Chen Yilin Yang Jiahui Li Ying Xia Ya Peng Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer’s disease by regulating microglia homeostasis and inhibiting HMGB1 pathway Alzheimer’s Research & Therapy Alzheimer’s disease Cognitive impairment β-amyloid Neuroinflammation Delta-opioid receptor Microglia |
| title | Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer’s disease by regulating microglia homeostasis and inhibiting HMGB1 pathway |
| title_full | Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer’s disease by regulating microglia homeostasis and inhibiting HMGB1 pathway |
| title_fullStr | Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer’s disease by regulating microglia homeostasis and inhibiting HMGB1 pathway |
| title_full_unstemmed | Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer’s disease by regulating microglia homeostasis and inhibiting HMGB1 pathway |
| title_short | Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer’s disease by regulating microglia homeostasis and inhibiting HMGB1 pathway |
| title_sort | delta opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of alzheimer s disease by regulating microglia homeostasis and inhibiting hmgb1 pathway |
| topic | Alzheimer’s disease Cognitive impairment β-amyloid Neuroinflammation Delta-opioid receptor Microglia |
| url | https://doi.org/10.1186/s13195-025-01682-1 |
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