Novel Phenylethanoid Glycosides Improve Hippocampal Synaptic Plasticity via the Cyclic Adenosine Monophosphate-CREB-Brain-Derived Neurotrophic Growth Factor Pathway in APP/PS1 Transgenic Mice

Gerontology. 2023;69(9):1065-1075. doi: 10.1159/000531194. Epub 2023 Jun 7.

Abstract

Introduction: Alzheimer's disease (AD) is a major public health concern worldwide, but there are still no drugs available that treat it effectively. Previous studies have shown that phenylethanoid glycosides have pharmacological effects, which include anti-AD properties, but the underlying mechanisms by which they ameliorate AD symptoms remain unknown.

Methods: In this study, we used an APP/PS1 AD mouse model to explore the function and mechanisms underlying savatiside A (SA) and torenoside B (TB) in the treatment of AD. SA or TB (100 mg·kg-1·d-1) was orally administered to 7-month-old APP/PS1 mice for 4 weeks. Cognitive and memory functions were measured using behavioral experiments (including the Morris water maze test and the Y-maze spontaneous alternation test). Molecular biology experiments (including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays) were used to detect any corresponding changes in signaling pathways.

Results: The results showed that SA or TB treatment could significantly reduce cognitive impairment in APP/PS1 mice. We also showed that chronic treatment with SA/TB could prevent spine loss, synaptophysin immunoreactivity, and neuronal loss in mice, thereby improving synaptic plasticity and moderating learning and memory deficits. SA/TB administration also promoted the expression of synaptic proteins in APP/PS1 mouse brains and upregulated phosphorylation of proteins in the cyclic adenosine monophosphate (cAMP)/CREB/brain-derived neurotrophic growth factor (BDNF) pathway that are responsible for synaptic plasticity. Additionally, chronic SA/TB treatment increased the levels of BDNF and nerve growth factor (NGF) in the brains of APP/PS1 mice. Both astrocyte and microglia volumes, as well as the generation of amyloid β, were also decreased in SA/TB-treated APP/PS1 mice compared to control APP/PS1 mice.

Conclusion: In summary, SA/TB treatment was associated with activation of the cAMP/CREB/BDNF pathway and increased BDNF and NGF expression, indicating that SA/TB improves cognitive functioning via nerve regeneration. SA/TB is a promising candidate drug for the treatment of AD.

Keywords: Alzheimer’s disease; Cyclic adenosine monophosphate-signaling pathway; Neurotrophy; Phenylethanoid glycosides; Synapse plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / metabolism
  • Adenosine Monophosphate / pharmacology
  • Adenosine Monophosphate / therapeutic use
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides* / metabolism
  • Animals
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / metabolism
  • Disease Models, Animal
  • Hippocampus / metabolism
  • Maze Learning
  • Mice
  • Mice, Transgenic
  • Nerve Growth Factor / metabolism
  • Nerve Growth Factor / pharmacology
  • Nerve Growth Factor / therapeutic use
  • Neuronal Plasticity

Substances

  • Amyloid beta-Peptides
  • Brain-Derived Neurotrophic Factor
  • Nerve Growth Factor
  • Adenosine Monophosphate

Grants and funding

This work was supported by the Natural Science Foundation of Jiangsu Province (SBK20200213), Suzhou introduction of clinical medical team project (SZYJTD201802), Suzhou key medical support discipline (SZFCXK202111), Suzhou High-tech District Health Talents Project SGXWS2021, Suzhou Science and Technology Plan Project (SYSD2019171, SKJY2021035, SYS2020076, SKJY2021037), and the Plan Project (NMUB2020252) from Nanjing Medical University.