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 language | English (US) |
|---|---|
| Pages (from-to) | 57-61 |
| Number of pages | 5 |
| Journal | Journal of Molecular Neuroscience |
| Volume | 19 |
| Issue number | 1-2 |
| State | Published - Aug 2002 |
| Externally published | Yes |
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Keywords
- Alzheimer
- Beta amyloid
- Intracellular Aβ
- Neuronal death
- Toxicity
- Tricyclic pyrone
ASJC Scopus subject areas
- Neuroscience(all)
- Biochemistry
- Genetics
Cite this
Novel tricyclic pyrone compounds prevent intracellular APP C99-induced cell death. / Jin, Lee-Way; Hua, D. H.; Shie, F. S.; Maezawa, Izumi; Sopher, B.; Martin, G. M.
In: Journal of Molecular Neuroscience, Vol. 19, No. 1-2, 08.2002, p. 57-61.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel tricyclic pyrone compounds prevent intracellular APP C99-induced cell death
AU - Jin, Lee-Way
AU - Hua, D. H.
AU - Shie, F. S.
AU - Maezawa, Izumi
AU - Sopher, B.
AU - Martin, G. M.
PY - 2002/8
Y1 - 2002/8
N2 - 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.
AB - 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.
KW - Alzheimer
KW - Beta amyloid
KW - Intracellular Aβ
KW - Neuronal death
KW - Toxicity
KW - Tricyclic pyrone
UR - http://www.scopus.com/inward/record.url?scp=0036674070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036674070&partnerID=8YFLogxK
M3 - Article
C2 - 12212794
AN - SCOPUS:0036674070
VL - 19
SP - 57
EP - 61
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
SN - 0895-8696
IS - 1-2
ER -