Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer's disease mouse model and proteomics analysis

Xinhua Zhou; Kaipeng Huang; Yuqiang Wang; Zaijun Zhang; Yingying Liu; Qinghua Hou; Xifei Yang; Maggie Pui Man Hoi

doi:10.3389/fphar.2023.1082602

Evaluation of therapeutic effects of tetramethylpyrazine nitrone in Alzheimer's disease mouse model and proteomics analysis

Front Pharmacol. 2023 Mar 6:14:1082602. doi: 10.3389/fphar.2023.1082602. eCollection 2023.

Authors

Xinhua Zhou^{1

2

3}, Kaipeng Huang³, Yuqiang Wang^{1

4}, Zaijun Zhang⁴, Yingying Liu⁵, Qinghua Hou⁶, Xifei Yang⁷, Maggie Pui Man Hoi^{2

8}

Affiliations

¹ Department of Neurology and Stroke Center, Jinan University College of Pharmacy, The First Affiliated Hospital of Jinan University and Institute of New Drug Research, Guangzhou, China.
² State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinse Medical Sciences, University of Macau, Macau, China.
³ Institute of GCP, Guangzhou Eighth People's Hospital Guangzhou Medical University, Guangzhou, China.
⁴ Guangdong Province Key Laboratory of Pharmacodynamic, College of Pharmacy, Institute of New Drug Research, Constituents of Traditional Chinese Medicine & New Drug Research, Jinan University, Guangdong, China.
⁵ Department of Neurology, Daqing People's Hospital, Daqing, China.
⁶ Department of Neurology, Clinical Neuroscience Center, the 7th Affiliated Hospital, Sun-Yat-sen University. Shenzhen, China.
⁷ Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
⁸ DPS, Faculty of Health Sciences, University of Macau, Macau, China.

Abstract

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.

Keywords: PINK1; alhzheimer disease; amyloid beta; proteomic analysis; tetramethylpyrazine nitrone.

Grants and funding

This work was funded partially by The Science and Technology Development Fund, Macau SAR (0023/2020/AFJ, 0035/2020/AGJ), China Postdoctoral Science Foundation (2020M673086), National Natural Science Foundation of China (NSFC) (Project No. 82171583), The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission (JCYJ20200109150717745 XY), the Science and Technology Program of Guangzhou, China (202102020192), Science and Technology Plan of Heilongjiang Provincial Health Commission (20210303070032), and General Project of Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515010111).