Novel tricyclic pyrone compounds prevent intracellular APP C99-induced cell death.
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-beta protein (A beta is the major component of amyloid plaques and is derived from a larger transmembrane glycoprotein, termed amyloid beta protein precursor (APP), by proteolysis. The AD research has focused on A beta production and metabolism, its extracellular deposition, and its cellular toxicity. Recent evidence, however, suggests that A beta 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 A beta/CTF rather than on extracellular plaque formation. Accordingly, we propose that one of the primary targets of therapeutic intervention should be intracellular A beta/CTF and its toxic cellular effect. We have established a cell-culture model in which the neurons degenerate on induction of endogenous expression of A beta/CTF of APP. These cultures have been used to test whether tricyclic pyrone (TP) compounds may prevent A beta/CTF-mediated neuronal death. The results to date have been encouraging. Lead compounds will now be selected for their abilities to ameliorate A beta/CTF-mediated pathology in transgenic mice. Our hope is that these compounds may eventually prove beneficial for the prevention and treatment of AD.
Jin
Lee-Way
LW
Department of Pathology, University of Washington, Seattle 98195-7470, USA. lwjin@u.washington.edu
Hua
Duy H
DH
Shie
Feng-Shiun
FS
Maezawa
Izumi
I
Sopher
Bryce
B
Martin
George M
GM
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D015153:Blotting, Western; D016923:Cell Death; D002470:Cell Survival; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D011753:Pyrones / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011753:Pyrones