PMID- 24863668
OWN - NLM
STAT- MEDLINE
DCOM- 20150209
LR  - 20220318
IS  - 1558-1497 (Electronic)
IS  - 0197-4580 (Linking)
VI  - 35
IP  - 10
DP  - 2014 Oct
TI  - Iron overload accelerates neuronal amyloid-beta production and cognitive impairment 
      in transgenic mice model of Alzheimer's disease.
PG  - 2288-301
LID - S0197-4580(14)00321-2 [pii]
LID - 10.1016/j.neurobiolaging.2014.04.019 [doi]
AB  - Iron dyshomeostasis is proving increasingly likely to be involved in the 
      pathology of Alzheimer's disease (AD); yet, its mechanism is not well understood. 
      Here, we investigated the AD-related mechanism(s) of iron-sulfate exposure in 
      vitro and in vivo, using cultured primary cortical neurons and APP/PS1 AD-model 
      mice, respectively. In both systems, we observed iron-induced disruptions of 
      amyloid precursor protein (APP) processing, neuronal signaling, and cognitive 
      behavior. Iron overload increased production of amyloidogenic KPI-APP and amyloid 
      beta. Further, this APP misprocessing was blocked by MK-801 in vitro, suggesting 
      the effect was N-methyl-D-aspartate receptor (NMDAR) dependent. Calcium imaging 
      confirmed that 24 hours iron exposure led to disrupted synaptic signaling by 
      augmenting GluN2B-containing NMDAR expression-GluN2B messenger RNA and protein 
      levels were increased and promoting excessing extrasynaptic NMDAR signaling. The 
      disrupted GluN2B expression was concurrent with diminished expression of the 
      splicing factors, sc35 and hnRNPA1. In APP/PS1 mice, chronic iron treatment led 
      to hastened progression of cognitive impairment with the novel object recognition 
      discrimination index, revealing a deficit at the age of 4 months, concomitant 
      with augmented GluN2B expression. Together, these data suggest iron-induced APP 
      misprocessing and hastened cognitive decline occur through inordinate 
      extrasynaptic NMDAR activation.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Becerril-Ortega, Javier
AU  - Becerril-Ortega J
AD  - INSERM, U836, BP 170, Grenoble Cedex 9, F-38042, France; Universite Joseph 
      Fourier, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, 
      France.
FAU - Bordji, Karim
AU  - Bordji K
AD  - Universite de Caen-Basse Normandie, GIP Cyceron, CNRS UMR 6301 ISTCT, CERVOxy 
      Group, Caen, France.
FAU - Freret, Thomas
AU  - Freret T
AD  - GMPc-EA4259, Universite de Caen Basse-Normandie, GIP Cyceron 14032, Caen, France.
FAU - Rush, Travis
AU  - Rush T
AD  - INSERM, U836, BP 170, Grenoble Cedex 9, F-38042, France; Universite Joseph 
      Fourier, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, 
      France.
FAU - Buisson, Alain
AU  - Buisson A
AD  - INSERM, U836, BP 170, Grenoble Cedex 9, F-38042, France; Universite Joseph 
      Fourier, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, 
      France. Electronic address: alain.buisson@ujf-grenoble.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140501
PL  - United States
TA  - Neurobiol Aging
JT  - Neurobiology of aging
JID - 8100437
RN  - 0 (Amyloid beta-Peptides)
SB  - IM
MH  - Alzheimer Disease/*metabolism/*psychology
MH  - Amyloid beta-Peptides/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology
MH  - *Cognition
MH  - Cognition Disorders/*etiology
MH  - Disease Models, Animal
MH  - HEK293 Cells
MH  - Humans
MH  - Iron Overload/*complications/*metabolism/*psychology
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neurons/*metabolism
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Amyloid beta
OT  - GluN2B
OT  - Iron
OT  - NMDA
OT  - Transgenic mouse
EDAT- 2014/05/28 06:00
MHDA- 2015/02/11 06:00
CRDT- 2014/05/28 06:00
PHST- 2013/07/09 00:00 [received]
PHST- 2014/04/14 00:00 [revised]
PHST- 2014/04/22 00:00 [accepted]
PHST- 2014/05/28 06:00 [entrez]
PHST- 2014/05/28 06:00 [pubmed]
PHST- 2015/02/11 06:00 [medline]
AID - S0197-4580(14)00321-2 [pii]
AID - 10.1016/j.neurobiolaging.2014.04.019 [doi]
PST - ppublish
SO  - Neurobiol Aging. 2014 Oct;35(10):2288-301. doi: 
      10.1016/j.neurobiolaging.2014.04.019. Epub 2014 May 1.