title: RanBP9 overexpression accelerates loss of dendritic spines in a mouse model of Alzheimer's disease.
abstract: We previously demonstrated that RanBP9 overexpression increased Aβ generation and amyloid plaque burden, subsequently leading to robust reductions in the levels of several synaptic proteins as well as deficits in the learning and memory skills in a mouse model of Alzheimer's disease (AD). In the present study, we found striking reduction of spinophilin-immunoreactive puncta (52%, p<0.001) and spinophilin area (62.5%, p<0.001) in the primary cortical neurons derived from RanBP9 transgenic mice (RanBP9-Tg) compared to wild-type (WT) neurons. Similar results were confirmed in WT cortical neurons transfected with EGFP-RanBP9. At 6-months of age, the total spine density in the cortex of RanBP9 single transgenic, APΔE9 double transgenic and APΔE9/RanBP9 triple transgenic mice was similar to WT mice. However, in the hippocampus the spine density was significantly reduced (27%, p<0.05) in the triple transgenic mice compared to WT mice due to reduced number of thin spines (33%, p<0.05) and mushroom spines (22%, p<0.05). This suggests that RanBP9 overexpression in the APΔE9 mice accelerates loss of spines and that the hippocampus is more vulnerable. At 12-months of age, the cortex showed significant reductions in total spine density in the RanBP9 (22%, p<0.05), APΔE9 (19%, p<0.05) and APΔE9/RanBP9 (33%, p<0.01) mice compared to WT controls due to reductions in mushroom and thin spines. Similarly, in the hippocampus the total spine density was reduced in the RanBP9 (23%, p<0.05), APΔE9 (26%, p<0.05) and APΔE9/RanBP9 (39%, p<0.01) mice due to reductions in thin and mushroom spines. Most importantly, RanBP9 overexpression in the APΔE9 mice further exacerbated the reductions in spine density in both the cortex (14%, p<0.05) and the hippocampus (16%, p<0.05). Because dendritic spines are considered physical traces of memory, loss of spines due to RanBP9 provided the physical basis for the learning and memory deficits. Since RanBP9 protein levels are increased in AD brains, RanBP9 might play a crucial role in the loss of spines and synapses in AD.
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Wang
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Palavicini
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: University of Tennessee Health Science Center, Department of Neurology, 415 Link Building, TN, USA.
authors.forename: Panchanan
authors.initials: P
authors.lastname: Maiti
authors.affiliation: Laboratory of Immuneregulation, Department of Immunology, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Florida Institute of Technology, 150 West University Blvd, Melbourne, FL 32901, USA.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Biological Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: B N
authors.initials: BN
authors.lastname: Lloyd
authors.affiliation: Department of Biological Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Dawson-Scully
authors.affiliation: Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, 4001 E. Fletcher Ave. - MDC36, Tampa, FL 33612, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kang
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA. Electronic address: mlakshmana@tpims.org.
authors.forename: Madepalli K
authors.initials: MK
authors.lastname: Lakshmana
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000473:pathology / Q000502:physiology; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D049229:Dendritic Spines / Q000473:pathology / Q000502:physiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099273:Neurabins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000099273:Neurabins; C116005:Ran binding protein 9
keywords: APΔE9 mice; Cortex; Dendritic spines; Hippocampus; RanBP9; Transgenic mice