Selective neuronal degeneration induced by soluble oligomeric amyloid beta protein.
The prevailing amyloid hypothesis for Alzheimer's disease (AD) holds that amyloid beta-protein (Abeta) causes neuronal degeneration by forming neurotoxic fibrillar structures. Yet, many aspects of AD pathology and symptoms are not well explained by this hypothesis. Here, we present evidence that neurotoxicity of soluble oligomeric Abeta closely corresponds to the selective neurodegeneration so distinctly manifest in AD. Selectivity was first observed in vitro, where only the human central nervous system neuronal cells were susceptible to soluble oligomeric Abeta. Furthermore, in mouse cerebral slice treated with soluble oligomeric Abeta, selective regiospecific toxicity was evident in the hippocampal CA1, a division important for memory, but not in the CA3 subfield. The fibrillar Abeta, however, killed neurons in all regions of the cerebral slice cultures and also in cerebellar slices. Remarkably, even at the highest soluble oligomeric Abeta concentrations, cerebellar neurons were completely spared, consistent with one of the hallmark features of AD pathology. Our observation of the selective neurodegeneration of soluble oligomeric Abeta to neurons involved in cognitive function may provide a new opportunity for the development of an effective AD therapy as well as elucidating the pathological mechanism of AD.
Kim
Hyeon-Jin
HJ
Research Division, Jinis Biopharmaceuticals Co., Chonju, Chonbuk, South Korea.
Chae
Soo-Cheon
SC
Lee
Dae-Kwon
DK
Chromy
Brett
B
Lee
Sam Cheol
SC
Park
Yeong-Chul
YC
Klein
William L
WL
Krafft
Grant A
GA
Hong
Seong-Tshool
ST
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002490:Central Nervous System / Q000166:cytology; D002531:Cerebellum / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D009474:Neurons / Q000187:drug effects
D016229:Amyloid beta-Peptides