Abstract
The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer's disease (AD). This toxicity is related to Aβ aggregation into oligomers, protofibrils and fibrils. Recent studies suggest that intracellular Aβ, which causes profound toxicity, could be one of the primary therapeutic targets in AD. So far, no compounds targeting intracellular Aβ have been identified. We have investigated the toxicity induced by intracellular Aβ in a neuroblastoma MC65 line and found that it was closely related to intracellular accumulation of oligomeric complexes of Aβ (Aβ-OCs). We further identified a cell-permeable tricyclic pyrone named CP2 that ameliorates this toxicity and significantly reduces the levels of Aβ-OCs. In aqueous solution, CP2 attenuates Aβ oligomerization and prevents the oligomer-induced death of primary cortical neurons. CP2 analogs represent a new class of promising compounds for the amelioration of Aβ toxicities within both intracellular and extracellular sites.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 57-67 |
| Number of pages | 11 |
| Journal | Journal of Neurochemistry |
| Volume | 98 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2006 |
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Keywords
- Alzheimer's disease
- Amyloid
- Intracellular
- Oligomer
- Small molecule
- Toxicity
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience
Cite this
A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-β oligomeric complexes. / Maezawa, Izumi; Hong, Hyun Seok; Wu, Hui Chuan; Battina, Srinivas K.; Rana, Sandeep; Iwamoto, Takeo; Radke, Gary A.; Pettersson, Erik; Martin, George M.; Hua, Duy H.; Jin, Lee-Way.
In: Journal of Neurochemistry, Vol. 98, No. 1, 07.2006, p. 57-67.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-β oligomeric complexes
AU - Maezawa, Izumi
AU - Hong, Hyun Seok
AU - Wu, Hui Chuan
AU - Battina, Srinivas K.
AU - Rana, Sandeep
AU - Iwamoto, Takeo
AU - Radke, Gary A.
AU - Pettersson, Erik
AU - Martin, George M.
AU - Hua, Duy H.
AU - Jin, Lee-Way
PY - 2006/7
Y1 - 2006/7
N2 - The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer's disease (AD). This toxicity is related to Aβ aggregation into oligomers, protofibrils and fibrils. Recent studies suggest that intracellular Aβ, which causes profound toxicity, could be one of the primary therapeutic targets in AD. So far, no compounds targeting intracellular Aβ have been identified. We have investigated the toxicity induced by intracellular Aβ in a neuroblastoma MC65 line and found that it was closely related to intracellular accumulation of oligomeric complexes of Aβ (Aβ-OCs). We further identified a cell-permeable tricyclic pyrone named CP2 that ameliorates this toxicity and significantly reduces the levels of Aβ-OCs. In aqueous solution, CP2 attenuates Aβ oligomerization and prevents the oligomer-induced death of primary cortical neurons. CP2 analogs represent a new class of promising compounds for the amelioration of Aβ toxicities within both intracellular and extracellular sites.
AB - The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer's disease (AD). This toxicity is related to Aβ aggregation into oligomers, protofibrils and fibrils. Recent studies suggest that intracellular Aβ, which causes profound toxicity, could be one of the primary therapeutic targets in AD. So far, no compounds targeting intracellular Aβ have been identified. We have investigated the toxicity induced by intracellular Aβ in a neuroblastoma MC65 line and found that it was closely related to intracellular accumulation of oligomeric complexes of Aβ (Aβ-OCs). We further identified a cell-permeable tricyclic pyrone named CP2 that ameliorates this toxicity and significantly reduces the levels of Aβ-OCs. In aqueous solution, CP2 attenuates Aβ oligomerization and prevents the oligomer-induced death of primary cortical neurons. CP2 analogs represent a new class of promising compounds for the amelioration of Aβ toxicities within both intracellular and extracellular sites.
KW - Alzheimer's disease
KW - Amyloid
KW - Intracellular
KW - Oligomer
KW - Small molecule
KW - Toxicity
UR - http://www.scopus.com/inward/record.url?scp=33745058712&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745058712&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2006.03862.x
DO - 10.1111/j.1471-4159.2006.03862.x
M3 - Article
C2 - 16805796
AN - SCOPUS:33745058712
VL - 98
SP - 57
EP - 67
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 1
ER -