Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation.

Abstract

Our previous studies showed that the green tea-derived polyphenolic compound (-)-epigallocatechin-3 gallate (EGCG) reduces amyloid-β (Aβ) production in both neuronal and mouse Alzheimer's disease (AD) models in concert with activation of estrogen receptor-α/phosphatidylinositide 3-kinase/protein kinase B (ERα/PI3K/Akt) signaling and anti-amyloidogenic amyloid precursor protein (APP) α-secretase (a disintegrin and metallopeptidase domain-10, ADAM10) processing. Since the gallate moiety in EGCG may correspond to the 7α position of estrogen, thereby facilitating ER binding, we extensively screened the effect of other gallate containing phenolic compounds on APP anti-amyloidogenic processing. Octyl gallate (OG; 10 µM), drastically decreased Aβ generation, in concert with increased APP α-proteolysis, in murine neuron-like cells transfected with human wild-type APP or "Swedish" mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). In accord with our previous study, these cleavage events were associated with increased ADAM10 maturation and reduced by blockade of ERα/PI3k/Akt signaling. To validate these findings in vivo, we treated Aβ-overproducing Tg2576 mice with OG daily for one week by intracerebroventricular injection and found decreased Aβ levels associated with increased sAPPα. These data indicate that OG increases anti-amyloidogenic APP α-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10, suggesting that this compound may be an effective treatment for AD.

• Authors: She-Qing Zhang, Darrell Sawmiller, Song Li, Kavon Rezai-Zadeh, Huayan Hou, Shufeng Zhou, Douglas Shytle, Brian Giunta, Frank Fernandez, Takashi Mori, Jun Tan
• Journal: PloS one (PLoS One) Vol. 8 Issue 8 Pg. e71913 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23977176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• Estrogen Receptor alpha
• Membrane Proteins
• octyl gallate
• Gallic Acid
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Amyloid Precursor Protein Secretases
• ADAM Proteins
• ADAM10 Protein
• Adam10 protein, mouse

Topics

• ADAM Proteins (metabolism)
• ADAM10 Protein
• Alzheimer Disease (drug therapy, metabolism)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Cell Line, Tumor
• Drug Evaluation, Preclinical
• Enzyme Activation (drug effects)
• Estrogen Receptor alpha (antagonists & inhibitors, metabolism)
• Female
• Gallic Acid (analogs & derivatives, pharmacology)
• Humans
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Transgenic
• Phosphatidylinositol 3-Kinases (metabolism)
• Proteolysis
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction