PMS777, a new cholinesterase inhibitor with anti-platelet activated factor activity, regulates amyloid precursor

Hong-Qi Yang1, Zhi-Kun Sun, Yan-Xin Zhao

  • 1Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.

Neurochemical Research
|September 2, 2008
PubMed

Insights

PMS777, a novel drug, reduces beta-amyloid (Abeta) production by modulating amyloid precursor protein (APP) processing. This suggests PMS777 may offer therapeutic potential for Alzheimer's disease (AD).

Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) is a neurodegenerative disorder marked by memory and cognitive decline.
  • The beta-amyloid (Abeta) cascade is a key factor in AD pathophysiology.
  • Modulating amyloid precursor protein (APP) metabolism is a potential therapeutic strategy for AD.

Purpose of the Study:

  • To investigate the effects of PMS777, a cholinesterase inhibitor with anti-platelet activated factor activity, on APP processing.
  • To determine if PMS777 influences the generation of Abeta, a critical component in AD.

Main Methods:

  • Experiments were conducted using SH-SY5Y(APP695) and PC12 cell lines.
  • Cells were treated with PMS777, and the secretion of sAPPalpha and Abeta42 was measured.
  • Receptor antagonists (scopolamine and alpha-bungarotoxin) were used to explore the mechanism of action.

Main Results:

  • PMS777 significantly decreased the secretion of sAPPalpha in both cell lines without affecting holoAPP synthesis.
  • PMS777 treatment reduced the release of Abeta42 in SH-SY5Y(APP695) cells.
  • Scopolamine pretreatment antagonized the effect of PMS777 on sAPPalpha secretion, while alpha-bungarotoxin did not.

Conclusions:

  • PMS777 demonstrates the ability to modulate APP processing in vitro.
  • The drug's capacity to decrease Abeta generation indicates its potential therapeutic value for Alzheimer's disease.
  • The mechanism appears to involve M-receptor pathways.