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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025301/ https://www.ncbi.nlm.nih.gov/pubmed/36950017 http://dx.doi.org/10.3389/fphar.2023.1082602 |
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author | Zhou, Xinhua Huang, Kaipeng Wang, Yuqiang Zhang, Zaijun Liu, Yingying Hou, Qinghua Yang, Xifei Hoi, Maggie Pui Man |
author_facet | Zhou, Xinhua Huang, Kaipeng Wang, Yuqiang Zhang, Zaijun Liu, Yingying Hou, Qinghua Yang, Xifei Hoi, Maggie Pui Man |
author_sort | Zhou, Xinhua |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-10025301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100253012023-03-21 Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis Zhou, Xinhua Huang, Kaipeng Wang, Yuqiang Zhang, Zaijun Liu, Yingying Hou, Qinghua Yang, Xifei Hoi, Maggie Pui Man Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2023-03-06 /pmc/articles/PMC10025301/ /pubmed/36950017 http://dx.doi.org/10.3389/fphar.2023.1082602 Text en Copyright © 2023 Zhou, Huang, Wang, Zhang, Liu, Hou, Yang and Hoi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Zhou, Xinhua Huang, Kaipeng Wang, Yuqiang Zhang, Zaijun Liu, Yingying Hou, Qinghua Yang, Xifei Hoi, Maggie Pui Man Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer’s disease mouse model and proteomics analysis |
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 | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025301/ https://www.ncbi.nlm.nih.gov/pubmed/36950017 http://dx.doi.org/10.3389/fphar.2023.1082602 |
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