title: Extensive nuclear sphere generation in the human Alzheimer's brain.
abstract: Nuclear spheres are protein aggregates consisting of FE65, TIP60, BLM, and other yet unknown proteins. Generation of these structures in the cellular nucleus is putatively modulated by the amyloid precursor protein (APP), either by its cleavage or its phosphorylation. Nuclear spheres were preferentially studied in cell culture models and their existence in the human brain had not been known. Existence of nuclear spheres in the human brain was studied using immunohistochemistry. Cell culture experiments were used to study regulative mechanisms of nuclear sphere generation. The comparison of human frontal cortex brain samples from Alzheimer's disease (AD) patients to age-matched controls revealed a dramatically and highly significant enrichment of nuclear spheres in the AD brain. Costaining demonstrated that neurons are distinctly affected by nuclear spheres, but astrocytes never are. Nuclear spheres were predominantly found in neurons that were negative for threonine 668 residue in APP phosphorylation. Cell culture experiments revealed that JNK3-mediated APP phosphorylation reduces the amount of sphere-positive cells. The study suggests that nuclear spheres are a new APP-derived central hallmark of AD, which might be of crucial relevance for the molecular mechanisms in neurodegeneration.
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kolbe
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bukhari
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Loosse
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Leonhardt
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Glotzbach
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Pawlas
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hess
authors.affiliation: Department of Cytology, Institute of Anatomy, Ruhr University Bochum, Universitätsstraße 150, Bochum, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Theiss
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany. Electronic address: thorsten.t.mueller@rub.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Müller
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000502:physiology; D001921:Brain / Q000166:cytology* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D048057:Mitogen-Activated Protein Kinase 10 / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D066329:Protein Aggregates; D053484:RecQ Helicases / Q000378:metabolism*
chemical_list: C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D066329:Protein Aggregates; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D048057:Mitogen-Activated Protein Kinase 10; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: APP; Alzheimer's disease; BLM; FE65; TIP60; nuclear spheres