A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-beta oligomeric complexes.
The neurotoxicity of amyloid-beta protein (Abeta) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer's disease (AD). This toxicity is related to Abeta aggregation into oligomers, protofibrils and fibrils. Recent studies suggest that intracellular Abeta, which causes profound toxicity, could be one of the primary therapeutic targets in AD. So far, no compounds targeting intracellular Abeta have been identified. We have investigated the toxicity induced by intracellular Abeta in a neuroblastoma MC65 line and found that it was closely related to intracellular accumulation of oligomeric complexes of Abeta (Abeta-OCs). We further identified a cell-permeable tricyclic pyrone named CP2 that ameliorates this toxicity and significantly reduces the levels of Abeta-OCs. In aqueous solution, CP2 attenuates Abeta oligomerization and prevents the oligomer-induced death of primary cortical neurons. CP2 analogs represent a new class of promising compounds for the amelioration of Abeta toxicities within both intracellular and extracellular sites.
Maezawa
Izumi
I
MIND Institute and Department of Pathology, University of California Davis, Sacramento, California, USA.
Hong
Hyun-Seok
HS
Wu
Hui-Chuan
HC
Battina
Srinivas K
SK
Rana
Sandeep
S
Iwamoto
Takeo
T
Radke
Gary A
GA
Pettersson
Erik
E
Martin
George M
GM
Hua
Duy H
DH
Jin
Lee-Way
LW
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D002219:Carbamates / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects*; D018625:Microscopy, Atomic Force / Q000379:methods; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D020349:Surface Plasmon Resonance / Q000379:methods; D013997:Time Factors
D016229:Amyloid beta-Peptides; C512450:CP2 compound; D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D018696:Neuroprotective Agents; D011753:Pyrones