Catalpol Ameliorates Neurotoxicity in N2a/APP695swe Cells and APP/PS1 Transgenic Mice

Neurotox Res. 2022 Aug;40(4):961-972. doi: 10.1007/s12640-022-00524-4. Epub 2022 Jun 14.

Abstract

Alzheimer's disease (AD) causes progressive decline of memory and cognitive deficits. Because of its complicated pathogenesis, the prevention and therapy of AD remain an enormous challenge. It has been reported that catalpol possessed neuroprotective effects against AD. However, the involved mechanism still needs to be intensively studied. Therefore, the effects of catalpol on N2a/APP695swe cells and APP/PS1 mice were identified in the current study. Catalpol could improve cytotoxicity according to CCK-8 assay and ameliorate cellular morphological changes in N2a/APP695swe cells. Neuronal structural damage in the hippocampal CA1 region of APP/PS1 AD mice was improved according to HE staining and immunohistochemistry of NeuN. Meanwhile, catalpol administration ameliorated cognitive deficits confirmed by behavior performance of APP/PS1 mice. Hoechst 33,342 staining and Annexin V-FITC/PI double staining demonstrated that catalpol could reduce apoptosis in N2a/APP695swe cells. Likewise, TUNEL staining also manifested that catalpol significantly reduced apoptosis in hippocampal CA1 region of APP/PS1 mice. Catalpol administration also could improve mitochondrial functions indicated by the ameliorative mitochondrial morphology, the decreased ROS generation, and the increased MMP in N2a/APP695swe cells. Subsequently, catalpol restrained oligomerization of Aβ1-42, verified by a reduced ThT fluorescence dose- and time-dependently. Additionally, both Aβ1-40 and Aβ1-42 aggregation were decreased in N2a/APP695swe cells and APP/PS1 mice administrated with catalpol confirmed by ELISA and western blot. Western blot also showed that catalpol facilitated the phosphorylation of AKT and GSK3β, and impeded the expression of BACE1 both in vivo and in vitro. Finally, a slight alteration in lactylation, 2-hydroxyisobutyrylation, and phosphorylation were found in N2a/APP695swe cells treated with catalpol. Together, these findings manifested that catalpol served a neuroprotective effect in AD and might be a novel and expecting prophylactic or curative candidate for AD or neurodegenerative diseases therapy.

Keywords: APP/PS1 transgenic mouse; Alzheimer’s disease; Catalpol; N2a/APP695swe Cells.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / toxicity
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Aspartic Acid Endopeptidases
  • Disease Models, Animal
  • Iridoid Glucosides
  • Mice
  • Mice, Transgenic
  • Neuroprotective Agents* / pharmacology
  • Neuroprotective Agents* / therapeutic use
  • Neurotoxicity Syndromes*
  • Presenilin-1 / genetics

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Iridoid Glucosides
  • Neuroprotective Agents
  • Presenilin-1
  • catalpol
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases