title: Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer's disease.
abstract: Double-transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mice express a chimeric mouse/human APP bearing the Swedish mutation (Mo/HuAPP695swe) and a mutant human PS1-dE9 both causative of familial Alzheimer's disease (FAD). Transgenic mice show impaired memory and learning performance from the age of 6 months onwards. Double-transgenic APP/PS1 mice express altered APP and PS1 mRNAs and proteins, reduced β-secretase 1 (BACE1) mRNA and normal BACE1 protein, all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD. The first β-amyloid plaques in APP/PS1 mice appear at 3 months, and they increase in number and distribution with disease progression in parallel with increased levels of brain soluble β-amyloid 1-42 and 1-40, but also with reduced 1-42/1-40 ratio with age. Amyloid deposition in plaques is accompanied by altered mitochondria and increased oxidative damage, post-translational modifications and accumulation of altered proteins at the dystrophic neurites surrounding plaques. Degradation pathways are also modified with disease progression including activation of the immunoproteasome together with variable alterations of the different protease activities of the ubiquitin-proteasome system. Present observations show modifications in the production of β-amyloid and activation and malfunction of the subcellular degradation pathways that have general implications in the pathogenesis of AD and more particularly in specificities of FAD amyloidogenesis.
authors.affiliation: Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Aso
authors.forename: Selene
authors.initials: S
authors.lastname: Lomoio
authors.forename: Irene
authors.initials: I
authors.lastname: López-González
authors.forename: Laura
authors.initials: L
authors.lastname: Joda
authors.forename: Margarita
authors.initials: M
authors.lastname: Carmona
authors.forename: Núria
authors.initials: N
authors.lastname: Fernández-Yagüe
authors.forename: Jesús
authors.initials: J
authors.lastname: Moreno
authors.forename: Salvador
authors.initials: S
authors.lastname: Juvés
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.forename: Virginia
authors.initials: V
authors.lastname: Martín
authors.forename: Mario
authors.initials: M
authors.lastname: Díaz
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001362:Avoidance Learning / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D003072:Cognition Disorders / Q000209:etiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D016253:Microscopy, Immunoelectron; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation / Q000235:genetics; D009483:Neuropsychological Tests; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D053764:Presenilin-1 / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; C000606290:SOD1 protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; C071313:LMP-2 protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020928:Mitogen-Activated Protein Kinases; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; D046988:Proteasome Endopeptidase Complex; C490920:Psmb10 protein, mouse