title: Role of RanBP9 on amyloidogenic processing of APP and synaptic protein levels in the mouse brain.
abstract: We previously reported that RanBP9 binds low-density lipoprotein receptor-related protein (LRP), amyloid precursor protein (APP), and BACE1 and robustly increased Aβ generation in a variety of cell lines and primary neuronal cultures. To confirm the physiological/ pathological significance of this phenotype in vivo, we successfully generated transgenic mice overexpressing RanBP9 as well as RanBP9-null mice. Here we show that RanBP9 overexpression resulted in >2-fold increase in Aβ40 levels as early as 4 mo of age. A sustained increase in Aβ40 levels was seen at 12 mo of age in both CHAPS-soluble and formic acid (FA)-soluble brain fractions. In addition, Aβ42 levels were also significantly increased in FA-soluble fractions at 12 mo of age. More important, increased Aβ levels were translated to increased deposition of amyloid plaques. In addition, RanBP9 overexpression significantly decreased the levels of synaptophysin and PSD-95 proteins. Conversely, RanBP9-null mice showed increased levels of synaptophysin, PSD-95, and drebrin A protein levels. Given that loss of synapses is the best pathological correlate of cognitive deficits in Alzheimer's disease (AD), increased Aβ levels by RanBP9 observed in the present study provides compelling evidence that RanBP9 may indeed play a key role in the etiology of AD. If so, RanBP9 provides a great opportunity to develop novel therapy for AD.
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida, USA. mlakshmana@tpims.org
authors.forename: Madepalli K
authors.initials: MK
authors.lastname: Lakshmana
authors.forename: Crystal D
authors.initials: CD
authors.lastname: Hayes
authors.forename: Steven P
authors.initials: SP
authors.lastname: Bennett
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.forename: Konda M
authors.initials: KM
authors.lastname: Reddy
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
authors.forename: David E
authors.initials: DE
authors.lastname: Kang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C116005:Ran binding protein 9