Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis
The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest...
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1082602/full |
| _version_ | 1811159634452414464 |
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| author | Xinhua Zhou Xinhua Zhou Xinhua Zhou Kaipeng Huang Yuqiang Wang Yuqiang Wang Zaijun Zhang Yingying Liu Qinghua Hou Xifei Yang Maggie Pui Man Hoi Maggie Pui Man Hoi |
| author_facet | Xinhua Zhou Xinhua Zhou Xinhua Zhou Kaipeng Huang Yuqiang Wang Yuqiang Wang Zaijun Zhang Yingying Liu Qinghua Hou Xifei Yang Maggie Pui Man Hoi Maggie Pui Man Hoi |
| author_sort | Xinhua Zhou |
| collection | DOAJ |
| description | The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non-amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy. |
| first_indexed | 2024-04-10T05:44:27Z |
| format | Article |
| id | doaj.art-9ce91f4645dc48f3a0b250723e80eaf6 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T05:44:27Z |
| publishDate | 2023-03-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-9ce91f4645dc48f3a0b250723e80eaf62023-03-06T04:34:42ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-03-011410.3389/fphar.2023.10826021082602Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysisXinhua Zhou0Xinhua Zhou1Xinhua Zhou2Kaipeng Huang3Yuqiang Wang4Yuqiang Wang5Zaijun Zhang6Yingying Liu7Qinghua Hou8Xifei Yang9Maggie Pui Man Hoi10Maggie Pui Man Hoi11Department of Neurology and Stroke Center, Jinan University College of Pharmacy, The First Affiliated Hospital of Jinan University and Institute of New Drug Research, Guangzhou, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinse Medical Sciences, University of Macau, Macau, ChinaInstitute of GCP, Guangzhou Eighth People’s Hospital Guangzhou Medical University, Guangzhou, ChinaInstitute of GCP, Guangzhou Eighth People’s Hospital Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurology and Stroke Center, Jinan University College of Pharmacy, The First Affiliated Hospital of Jinan University and Institute of New Drug Research, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmacodynamic, College of Pharmacy, Institute of New Drug Research, Constituents of Traditional Chinese Medicine & New Drug Research, Jinan University, Guangdong, ChinaGuangdong Province Key Laboratory of Pharmacodynamic, College of Pharmacy, Institute of New Drug Research, Constituents of Traditional Chinese Medicine & New Drug Research, Jinan University, Guangdong, ChinaDepartment of Neurology, Daqing People’s Hospital, Daqing, ChinaDepartment of Neurology, Clinical Neuroscience Center, the 7th Affiliated Hospital, Sun-Yat-sen University. Shenzhen, ChinaKey Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinse Medical Sciences, University of Macau, Macau, ChinaDPS, Faculty of Health Sciences, University of Macau, Macau, ChinaThe pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non-amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.https://www.frontiersin.org/articles/10.3389/fphar.2023.1082602/fullalhzheimer diseasetetramethylpyrazine nitroneamyloid betaproteomic analysisPINK1 |
| spellingShingle | Xinhua Zhou Xinhua Zhou Xinhua Zhou Kaipeng Huang Yuqiang Wang Yuqiang Wang Zaijun Zhang Yingying Liu Qinghua Hou Xifei Yang Maggie Pui Man Hoi Maggie Pui Man Hoi Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis Frontiers in Pharmacology alhzheimer disease tetramethylpyrazine nitrone amyloid beta proteomic analysis PINK1 |
| title | Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis |
| title_full | Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis |
| title_fullStr | Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis |
| title_full_unstemmed | Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis |
| title_short | Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis |
| title_sort | evaluation of therapeutic effects of tetramethylpyrazine nitrone in alzheimer s disease mouse model and proteomics analysis |
| topic | alhzheimer disease tetramethylpyrazine nitrone amyloid beta proteomic analysis PINK1 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1082602/full |
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