Amyloid beta 1-42 (A beta 1-42) Induces the CDK2-MediatedPhosphorylation of Tau through the Activation of the mTORC1 SignalingPathway While Promoting Neuronal Cell Death

Collection with item attached
2017
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/474498.do
DOI
10.3389/fnmol.2017.00229
Title
Amyloid beta 1-42 (A beta 1-42) Induces the CDK2-MediatedPhosphorylation of Tau through the Activation of the mTORC1 SignalingPathway While Promoting Neuronal Cell Death
Description
This research was supported by National R&D Program through the NationalResearch Foundation of Korea (NRF) funded by the Ministry of Science,ICT and Future Planning (NRF-2013M3A9B4076541).
abstract
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment and memory loss. Amyloid beta 1-42 (A beta) and hyper-phosphorylation of microtubule-associated protein tau have been considered as major histological features in AD. However, the mechanism of how Ab induces the hyper-phosphorylation of tau remains to be clarified. In the present study, we investigated the underlying cellular mechanisms of A beta with regard to the cell cycle regulatory protein-mediated phosphorylation of tau in promoting neuronal cell death. The oligomer A beta (5 mu M) significantly increased the level of caspase 3 cleavage and has the ability to induce cytotoxicity in human neuroblastoma SK-N-MC cells. A beta induced the degree of extracellular calcium influx via the L-type channel to facilitate the production of reactive oxygen species (ROS). A beta signaling through ROS production is uniquely mediated by the activation of PI3K/Akt, which is in turn required for mammalian target of rapamycin complex 1 (mTORC1) phosphorylation. mTORC1 activated by A beta further increased the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a binding protein (4E-BP1) and p70S6K1 to stimulate the HIF1 alpha synthesis responsible for the induction of cyclinD(1)/cyclin-dependent kinase 4 (CDK4) and cyclinE/CDK2, whereas it significantly attenuated the activation of autophagy. A beta distinctively induced the CDK2-mediated phosphorylation of tau, which is responsible for microtubule destabilization in promoting neuronal apoptosis. In mouse hippocampal primary neurons, the apoptotic cell death induced by A beta is highly susceptible to the mTORC1 signaling pathway. These results demonstrate that A beta efficiently stimulates the mTORC1 signaling pathway to facilitate HIF1 alpha synthesis and autophagy inhibition to promote the expression of cell cycle regulatory proteins, during which CDK2 uniquely stimulates tau phosphorylation for microtubule destab
provenance
Made available in Cube on 2018-09-28T10:47:39Z (GMT). No. of bitstreams: 0
language
English
author
Lee, Ki Hoon
Lee, Sei-Jung
Lee, Hyun Jik
Choi, Gee Euhn
Jung, Young Hyun
Kim, Dah Ihm
Gabr, Amr Ahmed
Ryu, Jung Min
Han, Ho Jae
orcid
Han, Ho Jae/0000-0002-0657-1766
accessioned
2018-09-28T10:47:39Z
available
2018-09-28T10:47:39Z
issued
2017
citation
FRONTIERS IN MOLECULAR NEUROSCIENCE(10)
issn
1662-5099
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/474498.do
Funder
과학기술정보통신부
Funding Program
바이오.의료기술개발
Project ID
1711057678
Jurisdiction
Rep.of Korea
Project Name
Production of functional differentiated cell via controlling nutrient sensor in stem cells
rights
openAccess
subject
Alzheimer's disease
mammalian target of rapamycin
cyclin dependentkinase 2
tauopathy
neuronal cell death
type
article


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