Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

被引:171
作者
Pigino, G. [1 ,4 ]
Morfini, G. [1 ,4 ]
Atagi, Y. [1 ,4 ]
Deshpande, A. [2 ,3 ]
Yu, C. [1 ]
Jungbauer, L. [1 ]
LaDu, M. [1 ]
Busciglio, J. [2 ,3 ]
Brady, S. [1 ,4 ]
机构
[1] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL 60612 USA
[2] Univ Calif Irvine, Dept Neurobiol, Irvine, CA 92697 USA
[3] Univ Calif Irvine, Dept Behav, Irvine, CA 92697 USA
[4] Marine Biol Lab, Woods Hole, MA 02543 USA
基金
美国国家卫生研究院;
关键词
Alzheimer's disease; Axonal transport; Beta amyloid oligomer; CK2; Kinesin; PROTEIN-KINASE CK2; KINESIN HEAVY-CHAIN; ALZHEIMERS-DISEASE; A-BETA; ANDROGEN RECEPTOR; PRECURSOR PROTEIN; HUMAN NEURONS; BRAIN; MUTATIONS; OLIGOMERS;
D O I
10.1073/pnas.0901229106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The pathological mechanism by which A beta causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric A beta (oA beta) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oA beta showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oA beta was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oA beta on FAT. Both oA beta and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD.
引用
收藏
页码:5907 / 5912
页数:6
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