title: COPS5 protein overexpression increases amyloid plaque burden, decreases spinophilin-immunoreactive puncta, and exacerbates learning and memory deficits in the mouse brain.
abstract: Brain accumulation of neurotoxic amyloid β (Aβ) peptide because of increased processing of amyloid precursor protein (APP), resulting in loss of synapses and neurodegeneration, is central to the pathogenesis of Alzheimer disease (AD). Therefore, the identification of molecules that regulate Aβ generation and those that cause synaptic damage is crucial for future therapeutic approaches for AD. We demonstrated previously that COPS5 regulates Aβ generation in neuronal cell lines in a RanBP9-dependent manner. Consistent with the data from cell lines, even by 6 months, COPS5 overexpression in APΔE9 mice (APΔE9/COPS5-Tg) significantly increased Aβ40 levels by 32% (p < 0.01) in the cortex and by 28% (p < 0.01) in the hippocampus, whereas the increases for Aβ42 were 37% (p < 0.05) and 34% (p < 0.05), respectively. By 12 months, the increase was even more robust. Aβ40 levels increased by 63% (p < 0.001) in the cortex and by 65% (p < 0.001) in the hippocampus. Similarly, Aβ42 levels were increased by 69% (p < 0.001) in the cortex and by 71% (p < 0.011) in the hippocampus. Increased Aβ levels were translated into an increased amyloid plaque burden both in the cortex (54%, p < 0.01) and hippocampus (64%, p < 0.01). Interestingly, COPS5 overexpression increased RanBP9 levels in the brain, which, in turn, led to increased amyloidogenic processing of APP, as reflected by increased levels of sAPPβ and decreased levels of sAPPα. Furthermore, COPS5 overexpression reduced spinophilin in both the cortex (19%, p < 0.05) and the hippocampus (20%, p < 0.05), leading to significant deficits in learning and memory skills. Therefore, like RanBP9, COPS5 also plays a pivotal role in amyloid pathology in vivo.
authors.affiliation: From the Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida 34987.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Wang
authors.affiliation: From the Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida 34987.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: the Department of Neuroscience, Euroespes Biotechnology, Poligono de Bergondo, Nave F, 15165A, A Coruna, Spain, and.
authors.forename: Ivan
authors.initials: I
authors.lastname: Carrera
authors.affiliation: the Florida Institute of Technology, Melbourne, Florida 32901.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.affiliation: From the Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida 34987, mlakshmana@tpims.org.
authors.forename: Madepalli K
authors.initials: MK
authors.lastname: Lakshmana
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000075686:COP9 Signalosome Complex; D004797:Enzyme-Linked Immunosorbent Assay; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007859:Learning Disabilities / Q000378:metabolism*; D008569:Memory Disorders / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism*; D000099273:Neurabins
chemical_list: D000075686:COP9 Signalosome Complex; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010447:Peptide Hydrolases; D000099273:Neurabins; C501490:Cops5 protein, mouse
keywords: Alzheimer Disease; Amyloid Plaque Burden; Amyloid Precursor Protein (APP); COPS5; Jab1; Learning and Memory; Protein Processing; Spinophilin; Synaptic Plasticity; amyloid β (AB)