title: RanBP9 overexpression down-regulates phospho-cofilin, causes early synaptic deficits and impaired learning, and accelerates accumulation of amyloid plaques in the mouse brain.
abstract: Loss of synaptic proteins and functional synapses in the brains of patients with Alzheimer's disease (AD) as well as transgenic mouse models expressing amyloid-β protein precursor is now well established. However, the earliest age at which such loss of synapses occurs, and whether known markers of AD progression accelerate functional deficits is completely unknown. We previously showed that RanBP9 overexpression leads to enhanced amyloid plaque burden in a mouse model of AD. In this study, we found significant reductions in the levels of synaptophysin and spinophilin, compared with wild-type controls, in both the cortex and the hippocampus of 5- and 6-month old but not 3- or 4-month old APΔE9/RanBP9 triple transgenic mice, and not in APΔE9 double transgenic mice, nor in RanBP9 single transgenic mice. Interestingly, amyloid plaque burden was also increased in the APΔE9/RanBP9 mice at 5-6 months. Consistent with these results, we found significant deficits in learning and memory in the APΔE9/RanBP9 mice at 5 and 6 month. These data suggest that increased amyloid plaques and accelerated learning and memory deficits and loss of synaptic proteins induced by RanBP9 are correlated. Most importantly, APΔE9/RanBP9 mice also showed significantly reduced levels of the phosphorylated form of cofilin in the hippocampus. Taken together these data suggest that RanBP9 overexpression down-regulates cofilin, causes early synaptic deficits and impaired learning, and accelerates accumulation of amyloid plaques in the mouse brain.
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, FL, USA.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Palavicini
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, FL, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Peptide-based Therapeutics, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, FL, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Minond
authors.affiliation: Department of Immunology, Immunoregulation Unit, Institut Pasteur, Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Florida Institute of Technology, Melbourne, FL, USA.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, FL, USA.
authors.forename: Madepalli K
authors.initials: MK
authors.lastname: Lakshmana
mesh_terms: D051339:Actin Depolymerizing Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000009:adverse effects / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000009:adverse effects / Q000096:biosynthesis* / Q000235:genetics*; D015536:Down-Regulation / Q000502:physiology*; D007858:Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000009:adverse effects / Q000096:biosynthesis* / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
chemical_list: D051339:Actin Depolymerizing Factors; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C116005:Ran binding protein 9
keywords: Amyloid plaques; RanBP9; cofilin; learning and memory; spinophilin; synaptophysin