Flavanol-rich lychee fruit extract substantially reduces progressive cognitive and molecular deficits in a triple-transgenic animal model of Alzheimer disease

ABSTRACT

Effective treatment to prevent or arrest the advance of Alzheimer disease (AD) has yet to be discovered. We investigated whether Oligonol^R, an FDA-approved flavanol-rich extract prepared from lychee fruit and green tea, exerted beneficial effects relevant to AD in a triple transgenic male mouse model of AD (3×Tg-AD). At 9 months of age, untreated 3×Tg-AD mice vs. wild-type (WT) controls displayed cognitive deficits in behavioral assays and, at 12 months, elevated levels of hippocampal amyloid beta-protein (Aβ), amyloid precursor protein (APP), tau phosphorylation, and pro-inflammatory cytokines. 3×Tg-AD mice given Oligonol showed fewer cognitive deficits and attenuated pathological indices at 12 months. Oligonol treatment of 3×Tg-AD mice modulated expression of some critical brain proteins that involve multiple pathways relevant to mitochondrial dysfunction, proteasomal failure, endoplasmic reticulum (ER) stress and synaptic impairment. Together, these results demonstrate that continuous Oligonol treatment attenuates AD-like pathology and cognitive impairment of 3×Tg-AD mice and set the stage for clinical trials of this flavanol-rich plant extract in patients with early AD.

KEYWORDS:

• Alzheimer’s disease
• endoplasmic reticulum stress
• mitochondrial dysfunction
• Oligonol
• proteasomal failure
• synaptic loss
• amyloid beta
• tau phosphrolation
• inflammatory cytokines

Acknowledgements

X. C., L. N., and K. H. performed the animal studies. X. C., X. H. and L. Z. performed the biochemical evaluations and Western-blot analysis. X. C. and B. X. performed the proteomics study and drafted the manuscript. P. S., X. Y. and J. L supervised, designed all the studies, and revised the manuscript. The authors have no relationship with Amino Up Chemical Co, Ltd, Sapporo, Japan, the manufacturer and supplier of Oligonol^R.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Nature Science Foundation of China [grant number 81803209], Shenzhen Technical Project from Shenzhen Science and Technology Innovation Committee [grant number JCYJ20160428142632408] and Guangdong Natural Science Foundation [grant number 2017A030310617], and Sanming Project of Medicine in Shenzhen [grant number SZSM201611090].

Notes on contributors

Xiao Chen

Dr Xiao Chen obtained her doctor degree of philosophy from National University of Singapore in 2014 and joined Shenzhen Center for Disease Control and Prevention (SZCDC) as a postdoctoral fellow. Dr Chen has been selected as a young committee member of Neurotoxicology Committee, China Society of Toxicology. Her research area is etiology and intervention strategy of neurodegenerative diseases. She has published seven SCI papers and is the inventor of one US patent.

Benhong Xu

Dr Benhong Xu received his Ph.D. degree from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences in 2017. After he graduated, Dr Xu joined SZCDC as a postdoctoral fellow. His research interest is the pathogenesis of neurodegenerative diseases, biomarkers and drug activity evaluation and mechanism research of Alzheimer's disease. Dr Xu has published 16 SCI paper.

Luling Nie

Ms Luling Nie graduated from School of chemistry, Xiangtan University in 2017 and after that she joined SZCDC. She had published 4 papers related to drug screening and evaluation.

Kaiwu He

Mr Kaiwu He graduated from School of Pharmacy, Jinan University in 2017. He currently focuses on the basic research of neurodegenerative disorder. He had authored or co-authored five SCI papers.

Li Zhou

Ms Li Zhou is currently the deputy head of institute of toxicology, SZCDC. She graduated from Tongji Medical School, Huazhong University of Science and Technology in 2002 and after that she joined Shenzhen Center for Disease Control and Prevention. Ms Zhou has participated multiple research projects related to neurodegenerative diseases.

Xinfeng Huang

Ms Xinfeng Huang joined SZCDC in 1993. She has participated multiple research projects related to neurodegenerative diseases.

Peter Spencer

Dr Peter Spencer is currently the professor of Neurology of Oregon Health & Science University (OHSU). Dr Spencer is the Fellow of American Neurological Association and Royal College of Pathologists, besides he holds seven other honorary professorial appointments at foreign institutions. Dr Spencer received his doctoral degree from the University of London, Faculty of Medicine (Pathology) and postdoctoral training in neuroscience in the Rose F. Kennedy Center for Research on Mental Retardation and Human Development of the Albert Einstein College of Medicine (AECM). Dr Spencer has published over 400 research papers, including Science, the Lancet, and Nature methods, with over 18,000 citations. He is the founding director of Institute of Neurotoxicology, Albert Einstein College of Medicine, and OHSU Global Health Center.

Xifei Yang

Dr Xifei Yang is currently the deputy head of institute of toxicology, SZCDC. Dr Yang obtained his Ph.D. from Tongji Medical School, Huazhong University of Science and Technology, and his postdoctoral trainings from Hong Kong University and Harvard University. Dr Yang has focused on the environmental etiology of neurodegenerative diseases using OMICS technologies, which display unique advantages for revealing crucial signaling pathways disturbed by chemical toxins. Dr Yang has published over a hundred of scientific paper and he has been the associate editor of Journal of Alzheimers Disease and the editor of Frontiers in Neuroscience.

Jianjun Liu

Professor Jianjun Liu is currently the head of institute of toxicology, SZCDC. Prof Liu pioneered in establishing a proteomics research technology platform in Shenzhen. She has a broad research interest, including the molecular mechanism of biochemical damage caused by chemical pollutants, biomarker research, biosafety evaluation of nanomaterials, and research and development of food safety testing technology. Prof Liu supervised Dr Xiao Chen's postdoctoral training.