Gallic acid is a dual α/β-secretase modulator that reverses cognitive impairment and remediates pathology in Alzheimer mice.

Abstract

Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer's disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed. To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid β-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated Alzheimer-like pathology. At 18 months of age, GA therapy reversed impaired learning and memory as compared with vehicle, and did not alter behavior in nontransgenic littermates. GA-treated APP/PS1 mice had mitigated cerebral amyloidosis, including brain parenchymal and cerebral vascular β-amyloid deposits, and decreased cerebral amyloid β-proteins. Beneficial effects co-occurred with reduced amyloidogenic and elevated nonamyloidogenic APP processing. Furthermore, brain inflammation, gliosis, and oxidative stress were alleviated. We show that GA simultaneously elevates α- and reduces β-secretase activity, inhibits neuroinflammation, and stabilizes brain oxidative stress in a pre-clinical mouse model of AD. We further demonstrate that GA increases abundance of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, Adam10) proprotein convertase furin and activates ADAM10, directly inhibits β-site APP cleaving enzyme 1 (BACE1, Bace1) activity but does not alter Adam10 or Bace1 transcription. Thus, our data reveal novel post-translational mechanisms for GA. We suggest further examination of GA supplementation in humans will shed light on the exciting therapeutic potential of this molecule.

• Authors: Takashi Mori, Naoki Koyama, Tomotaka Yokoo, Tatsuya Segawa, Masahiro Maeda, Darrell Sawmiller, Jun Tan, Terrence Town
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 48 Pg. 16251-16266 (11 27 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 32913125 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Mori et al.

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• Furin protein, mouse
• Membrane Proteins
• PSEN1 protein, human
• Presenilin-1
• Gallic Acid
• Amyloid Precursor Protein Secretases
• Furin
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse
• ADAM10 Protein
• Adam10 protein, mouse

Topics

• ADAM10 Protein (genetics, metabolism)
• Alzheimer Disease (drug therapy, enzymology, genetics)
• Amyloid Precursor Protein Secretases (genetics, metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Aspartic Acid Endopeptidases (genetics, metabolism)
• Disease Models, Animal
• Furin (genetics, metabolism)
• Gallic Acid (pharmacology)
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Transgenic
• Presenilin-1 (genetics, metabolism)