Novel tricyclic pyrone compounds prevent intracellular APP C99-induced cell death

Lee-Way Jin, D. H. Hua, F. S. Shie, Izumi Maezawa, B. Sopher, G. M. Martin

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the progressive and global loss of cognitive functions. Pathological features include a loss of neurons in vulnerable brain regions and the extracellular deposition of abnormal protein aggregates known as amyloid plaques. Amyloid-β protein (Aβ is the major component of amyloid plaques and is derived from a larger transmembrane glycoprotein, termed amyloid β protein precursor (APP), by proteolysis. The AD research has focused on Aβ production and metabolism, its extracellular deposition, and its cellular toxicity. Recent evidence, however, suggests that Aβ as well as the C-terminal fragments (CTF) of APP can accumulate intraneuronally. The neuronal loss and synaptic transmission deficit in AD may therefore depend on intraneuronal accumulation of Aβ/CTF rather than on extracellular plaque formation. Accordingly, we propose that one of the primary targets of therapeutic intervention should be intracellular Aβ/CTF and its toxic cellular effect. We have established a cell-culture model in which the neurons degenerate on induction of endogenous expression of Aβ/CTF of APP. These cultures have been used to test whether tricyclic pyrone (TP) compounds may prevent Aβ/CTF-mediated neuronal death. The results to date have been encouraging. Lead compounds will now be selected for their abilities to ameliorate Aβ/CTF-mediated pathology in transgenic mice. Our hope is that these compounds may eventually prove beneficial for the prevention and treatment of AD.

Original languageEnglish (US)
Pages (from-to)57-61
Number of pages5
JournalJournal of Molecular Neuroscience
Volume19
Issue number1-2
StatePublished - Aug 2002
Externally publishedYes

Keywords

  • Alzheimer
  • Beta amyloid
  • Intracellular Aβ
  • Neuronal death
  • Toxicity
  • Tricyclic pyrone

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry
  • Genetics

Fingerprint Dive into the research topics of 'Novel tricyclic pyrone compounds prevent intracellular APP C99-induced cell death'. Together they form a unique fingerprint.

Cite this