Green Tea Epigallocatechin-3-Gallate (EGCG) and Other Flavonoids Reduce Alzheimer's Amyloid-Induced Mitochondrial Dysfunction

Article type: Research Article

Authors: Dragicevic, Natasa^{a; b} | Smith, Adam^{c; d; e} | Lin, Xiaoyang^f | Yuan, Fang^{f; g} | Copes, Neil^a | Delic, Vedad^a | Tan, Jun^{c; d; e; h; i} | Cao, Chuanhai^{a; e; f} | Shytle, R. Douglas^{c; e; i} | Bradshaw, Patrick C.^{a; *}

Affiliations: [a] Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA | [b] Department of Radiology, University of South Florida, Tampa, FL, USA | [c] Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, College of Medicine, University of South Florida, Tampa, Florida, USA | [d] Neuroimmunology Laboratory, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL, USA | [e] Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, Tampa, FL, USA | [f] Byrd Alzheimer's Center and Research Institute, Tampa, FL, USA | [g] Third Military Medical University, Chongqing, China | [h] Department of Psychiatry and Neurosciences, University of South Florida, Tampa, FL, USA | [i] Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, FL, USA

Correspondence: [*] Correspondence to: Patrick C. Bradshaw, Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 4202 E. Fowler Ave.; BSF 218, Tampa, FL, USA. Tel.: +813 974 6180; Fax: +813 974 1614; E-mail: [email protected].

Abstract: Amyloid-β (Aβ)-induced mitochondrial dysfunction may play a role in the onset and progression of Alzheimer's disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Plant-derived flavonoids have shown promise in improving certain AD phenotypes, but the overall mechanism of action(s) through which flavonoids protect from AD is still unknown. To identify flavonoids and other natural products that may correct amyloid-induced mitochondrial dysfunction, 25 natural products were screened for their ability to restore altered mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, or ATP levels in neuroblastoma cells expressing mutant amyloid-β protein precursor (AβPP). Epigallocatechin-3-gallate (EGCG) and luteolin were identified as the top two mitochondrial restorative compounds from the in vitro screen. EGCG was further tested in vivo to determine its effects on brain mitochondrial function in an AβPP/PS-1 (presenilin 1) double mutant transgenic mouse model of AD. EGCG treatment restored mitochondrial respiratory rates, MMP, ROS production, and ATP levels by 50 to 85% in mitochondria isolated from the hippocampus, cortex, and striatum. The results of this study lend further credence to the notion that EGCG and other flavonoids, such as luteolin, are ‘multipotent therapeutic agents’ that not only reduce toxic levels of brain Aβ, but also hold the potential to protect neuronal mitochondrial function in AD.

Keywords: Adenosine triphosphate, Alzheimer's disease, EGCG, flavonoids, membrane potential, mitochondrial, polyphenols, reactive oxygen species, respiration

DOI: 10.3233/JAD-2011-101629

Journal: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 507-521, 2011