Journal
NEUROBIOLOGY OF AGING
Volume 35, Issue 10, Pages 2288-2301Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.04.019
Keywords
Alzheimer's disease; Amyloid beta; Iron; NMDA; GluN2B; Transgenic mouse
Categories
Funding
- Fondation Neurodis
- Agence Nationale de la Recherche (ANR MALAAD program MALZ and TNT)
- Region Rhone-Alpes
- Javier Becerril-Ortega by the Region Basse Normandie
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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. (C) 2014 Elsevier Inc. All rights reserved.
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