Zhiyou Yang
Cai Song
Yue-Wei Ge
Chihiro Tohda- 1Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Institute of Nutrition and Marine Drugs, Guangdong Ocean University, Zhanjiang, China
- 2Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Guangdong Pharmaceutical University, Guangzhou, China
- 3Section of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama, Japan
Editorial on the Research Topic
Treatment of Alzheimer’s disease-discovery of natural products based on neurite outgrowth and neuroprotection
Alzheimer’s disease (AD) is an aging-related progressing neurodegenerative brain disorder. Extracellular neuritic plaques composed of misfolded amyloid β (Aβ) proteins and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein are the two typical characteristics of AD. Although AD has been reported for over 100 years, the intrinsic mechanism remains elusive and there are still no well-established clinical strategies to cure or even prevent this disease. Most of the designed molecules targeting Aβ and tau fail to improve cognitive function in clinical trials. Neurite atrophy and synaptic loss underlie the upstream of neuronal death and directly lead to memory impairment in AD (Dickson and Vickers, 2001). Thus, targeting neurite regeneration and synaptic reformation to reconstruct neuronal networks may provide promising therapeutic strategies for AD (Tohda, 2016). This research topic aimed to focus on natural products as novel therapeutics for AD based on neurite regeneration and neuroprotection.
The accumulation of Aβ oligomers promotes axonal transport impairment and follows mitochondrial dysfunction in the distal of neurites, leading to axonal degeneration (Salvadores et al., 2020). In addition, Ooi et al. demonstrated that glyceraldehyde-derived advanced glycation end-products (AGEs), involved in diabetes mellitus-associated AD, triggered tau hyperphosphorylation and abnormal aggregation of toxic AGE-β-tubulin complexes, thus inhibiting neurite outgrowth in human neuroblastoma SH-SY5Y cells. Meanwhile, the AGE inhibitor aminoguanidine and pyridoxamine inhibited the formation of AGE-β-tubulin complexes and mitigated the glyceraldehyde-induced suppression of neurite outgrowth.
Natural products are promising resources for AD intervention, a systematic strategy has been proposed to discover bioactive candidates in natural medicines based on neurite outgrowth, and subsequently to identify target proteins of bioactive compounds by means of drug affinity responsive target stability (DARTS) analysis (Yang et al., 2017). Furthermore, the saponins from Eleutherococcus senticosus showed neurite elongation effects in primary cultured cortical neurons and correlated with memory enhancement in normal rats, and 26 saponins were clarified penetrating the blood–brain barrier (Huang et al., 2022). Shi et al. investigated the memory ameliorative effects of baicalein, a well-known flavone, in Aβ42 hippocampal CA1 injected model mice. As a result, baicalein remarkably attenuated Aβ-induced neurite atrophy, spine loss, synaptic dysfunction, and cognitive deficits.
Glial cells play important roles in maintaining brain microenvironmental homeostasis. In response to Aβ stimuli, microglia NLRP3 assembles adaptor protein ASC and procaspase-1 into an inflammasome complex to induce the caspase-1 mediated secretion of IL-1β/IL-18, accompanied by a microglial switch from the protective M2 phenotype to the inflammatory M1 phenotype (Heneka et al., 2013). M1 microglia exerts low expression of degradation enzymes and decreased ability to engulf and degrade Aβ, resulting in increased Aβ deposits. While, naringenin, a natural flavanone, is able to transform the phenotype of M1 microglia to M2 microglia, and increase the expression of Aβ degradation enzymes including neprilysin and insulin degradation enzyme (Yang et al., 2019). The secreted IL-1β from M1 microglia triggers neuronal tau hyperphosphorylation via enhancing CaMKII-α and inhibiting PP2A activity (Ising et al., 2019). However, M2 microglia secreted IL-4 inhibits the phosphorylation of tau, thereafter, creating a beneficial microenvironment for the maintenance of regenerated axons. Tang et al. reported that a Chinese medicine formula 9002A ameliorated the increased expression of APP and memory deficits in an Aβ1-42 brain-injected mouse model. Sohn et al. investigated a food and medicinal plant, Ficus erecta, which could inhibit the activation of microglia and IL-1β production in icv Aβ1-42 injected mice. Furthermore, Aβ1-42-induced Aβ deposits, neuronal death, and cognitive impairment were also alleviated by Ficus erecta ethanol extracts treatment. In addition, Han et al. summarized the lignans, especially dibenzocyclooctene lignans, as potential anti-AD candidates for extensive pharmacological effects such as anti-neuroinflammation, neurite regeneration, and neuro-protection.
Collectively, neurite regeneration is essential for memory reconstruction, while modulating a beneficial microenvironment by removing toxic AGEs, Aβ plaques, phosphorylated tau protein, and inflammatory cytokines is required for the maintenance of regenerated neurites (Figure 1). Thus, muti-targeting therapies hold great potential to treat AD and traditional medicine-derived natural products precisely correspond to this characteristic.
FIGURE 1. Neurite regenerative strategy as potential AD therapy.
Author contributions
ZY wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Dickson, T. C., and Vickers, J. C. (2001). The morphological phenotype of β-amyloid plaques and associated neuritic changes in Alzheimer’s disease. Neuroscience 105, 99–107. doi:10.1016/s0306-4522(01)00169-5
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., et al. (2013). NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678. doi:10.1038/nature11729
Huang, Y. H., Ding, W. L., Li, X. T., Cai, M. T., Li, H. L., Yang, Z. Y., et al. (2022). Memory enhancement effect of saponins from Eleutherococcus senticosus leaves and blood-brain barrier-permeated saponins profiling using a pseudotargeted monitoring strategy. Food Funct. 13, 3603–3620. doi:10.1039/d1fo03078g
Ising, C., Venegas, C., Zhang, S., Scheiblich, H., Schmidt, S. V., Vieira-Saecker, A., et al. (2019). NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673. doi:10.1038/s41586-019-1769-z
Salvadores, N., Gerónimo-Olvera, C., and Court, F. A. (2020). Axonal degeneration in AD: The contribution of Aβ and tau. Front. Aging Neurosci. 12, 581767. doi:10.3389/fnagi.2020.581767
Tohda, C. (2016). New age therapy for alzheimer's disease by neuronal network reconstruction. Biol. Pharm. Bull. 39, 1569–1575. doi:10.1248/bpb.b16-00438
Yang, Z., Kuboyama, T., and Tohda, C. (2017). A systematic strategy for discovering a therapeutic drug for alzheimer's disease and its target molecule. Front. Pharmacol. 8, 340. doi:10.3389/fphar.2017.00340
Keywords: Alzheimer’s disease, natural products, neurite outgrowth, neuroprotection, anti-neuroinflammation, brain microenvironment
Citation: Yang Z, Song C, Ge Y-W and Tohda C (2022) Editorial: Treatment of Alzheimer’s disease-discovery of natural products based on neurite outgrowth and neuroprotection. Front. Pharmacol. 13:1079783. doi: 10.3389/fphar.2022.1079783
Received: 25 October 2022; Accepted: 31 October 2022;
Published: 18 November 2022.
Edited and reviewed by:
Nicholas M. Barnes, University of Birmingham, United KingdomCopyright © 2022 Yang, Song, Ge and Tohda. 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.
*Correspondence: Zhiyou Yang, yang_zhiyou@sina.com