title: Reduced neuronal signaling in the ageing apolipoprotein-E4 targeted replacement female mice.
abstract: The effect of ApoE on NMDAR-dependent ERK/CREB signaling is isoform-dependent, and ApoE4 accelerates memory decline in ageing. However, this isoform-dependent function on neuronal signaling during ageing is unclear. In this study, we have examined NMDAR-associated ERK/CREB signal transduction in young and aged huApoE3 and huApoE4 targeted replacement (TR) mice. At 12 weeks huApoE4 mouse brain, increased NR1-S896 phosphorylation was linked to higher protein kinase C (PKC) activation. This up-regulation was accompanied by higher phosphorylation of AMPA GluR1-S831, CaMKII, ERK1/2 and CREB. But at 32 weeks, there was no significant difference between huApoE3 and huApoE4 TR mice on NMDAR-associated ERK/CREB signaling. Interestingly, in 72-week-old huApoE4 TR mice, protein phosphorylation that were increased in younger mice were significantly reduced. Lower NR1-S896 phosphorylation was linked to reduced PKC, GluR1-S831, CaMKII, ERK1/2 and CREB phosphorylation in huApoE4 TR mice as compared to huApoE3 TR mice. Furthermore, we have consistently detected lower ApoE levels in young and aged huApoE4 TR mouse brain, and this was associated with reduced expression of the ApoE receptor, LRP1 and NR2A-Y1246 phosphorylation. These results suggest age-specific, isoform-dependent effects of ApoE on neuronal signaling.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Shan-May
authors.initials: SM
authors.lastname: Yong
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chian-Ming
authors.initials: CM
authors.lastname: Low
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Boon-Seng
authors.initials: BS
authors.lastname: Wong
mesh_terms: D000375:Aging / Q000235:genetics* / Q000502:physiology; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D020033:Protein Isoforms; D011973:Receptors, LDL / Q000096:biosynthesis*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
chemical_list: D053327:Apolipoprotein E4; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D020033:Protein Isoforms; D011973:Receptors, LDL; D016194:Receptors, N-Methyl-D-Aspartate; D025521:Tumor Suppressor Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2