title: Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer's disease.
abstract: 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.
authors.affiliation: INSERM, U836, BP 170, Grenoble Cedex 9, F-38042, France; Université Joseph Fourier, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France.
authors.forename: Javier
authors.initials: J
authors.lastname: Becerril-Ortega
authors.affiliation: Université de Caen-Basse Normandie, GIP Cyceron, CNRS UMR 6301 ISTCT, CERVOxy Group, Caen, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Bordji
authors.affiliation: GMPc-EA4259, Université de Caen Basse-Normandie, GIP Cyceron 14032, Caen, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fréret
authors.affiliation: INSERM, U836, BP 170, Grenoble Cedex 9, F-38042, France; Université Joseph Fourier, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France.
authors.forename: Travis
authors.initials: T
authors.lastname: Rush
authors.affiliation: INSERM, U836, BP 170, Grenoble Cedex 9, F-38042, France; Université Joseph Fourier, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France. Electronic address: alain.buisson@ujf-grenoble.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Buisson
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003071:Cognition; D003072:Cognition Disorders / Q000209:etiology*; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D019190:Iron Overload / Q000150:complications* / Q000378:metabolism* / Q000523:psychology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer's disease; Amyloid beta; GluN2B; Iron; NMDA; Transgenic mouse