Chlorogenic Acid Alleviates Aβ25-35-Induced Autophagy and Cognitive Impairment via the mTOR/TFEB Signaling Pathway

Drug Des Devel Ther. 2020 May 4:14:1705-1716. doi: 10.2147/DDDT.S235969. eCollection 2020.

Abstract

Purpose: Chlorogenic acid (CGA), a phenolic acid isolated from fruits and vegetables, has been established to have neuroprotective properties in relation to Alzheimer's disease (AD). However, the precise mechanism by which CGA prevents cognitive deficits in AD has not been well studied. This study aimed to explore the potential molecular mechanism of CGA action using an Aβ25-35-induced SH-SY5Y neuron injury and cogxnitive deficits model in APP/PS1 mice.

Methods: Three-month-old male APP/PS1 double transgenic mice and a human neuroblastoma cell line (SH-SY5Y) were used to assess the effects of CGA on AD in vivo and in vitro, respectively. Cognitive function in mice was measured using a Morris water maze (MWM) test. Hematoxylin and eosin, monodansylcadaverine fluorescence, LysoTracker Red (LTR), and immunofluorescence staining were used to evaluate the morphological changes in vivo and in vitro. The protein expressions of autophagy markers (LC3B-II/LC3B-I, p62/SQSTM, beclin1 and Atg5) and lysosomal-function-related markers (cathepsin D, mTOR, p-mTOR P70S6K, p-p70s6k and TFEB) were analyzed with Western blot analyses.

Results: CGA treatment significantly improved spatial memory, relieved neuron damage, and inhibited autophagy in APP/PS1 mice (P<0.05). Moreover, CGA notably suppressed autophagosome production and enhanced autophagy flux in SH-SY5Y cells induced by Aβ25-35 (P<0.05). Further analysis showed that CGA markedly promoted lysosomal activity, and this was accompanied by upregulated cathepsin D protein expression, which was induced by the mTOR/TFEB signaling pathway in APP/PS1 mice and Aβ25-35-exposed SH-SY5Y cells (P<0.05).

Conclusion: CGA treatment restored autophagic flux in the brain and alleviated cognitive impairments in APP/PS1 mice via enhanced activation of the mTOR/TFEB signaling pathway.

Keywords: TFEB; autophagy; chlorogenic acid; cognitive impairment.

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / prevention & control*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Autophagy / drug effects*
  • Cell Survival / drug effects
  • Chlorogenic Acid / administration & dosage
  • Chlorogenic Acid / pharmacology*
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / prevention & control*
  • Dose-Response Relationship, Drug
  • Humans
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Structure
  • Optical Imaging
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Signal Transduction / drug effects*
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Cells, Cultured

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (25-35)
  • Chlorogenic Acid
  • MTOR protein, human
  • TOR Serine-Threonine Kinases