title: Immunohistochemical analysis of ubiquilin-1 in the human hippocampus: association with neurofibrillary tangle pathology.
abstract: This post mortem immunohistochemical study examined the localization and distribution of ubiquilin-1 (UBL), a shuttle protein which interacts with ubiquitin and the proteasome, in the hippocampus from Alzheimer's disease (AD) dementia cases, and age-matched cases without dementia. In Braak stages 0-I-II cases, UBL immunoreactivity was detected in a dense fiber network in the neuropil, and in the cell cytoplasm and nucleoplasm of neurons in Cornu Ammonis (CA) fields and dentate gyrus granular neurons. In Braak stages III-IV and V-VI cases, UBL immunoreactivity was reduced in the neuropil and in the cytoplasm of the majority of CA1 neurons; some CA1 pyramidal neurons and the majority of CA2/3 pyramidal, CA4 multipolar, and dentate granular neurons had markedly increased UBL immunoreactivity in the nucleoplasm. Dual immunofluorescence analysis of UBL and antibody clone AT8 revealed co-localization most frequently in CA1 pyramidal neurons in Braak stage III-IV and V-VI cases. Further processing using the pan-amyloid marker X-34 revealed prominent UBL/X-34 dual labeling of extracellular NFT confined to the CA1/subiculum in Braak stage V-VI cases. Our results demonstrate that in AD hippocampus, early NFT changes are associated with neuronal up-regulation of UBL in nucleoplasm, or its translocation from the cytoplasm to the nucleus. The perseverance of UBL changes in CA2/3, CA4 and dentate gyrus, generally considered as more resistant to NFT pathology, but not in the CA1, may mark a compensatory, potentially protective response to increased tau phosphorylation in hippocampal neurons; the failure of such a response may contribute to neuronal degeneration in end-stage AD.
authors.affiliation: Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tokyo, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Mizukami
authors.forename: Eric E
authors.initials: EE
authors.lastname: Abrahamson
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Mi
authors.forename: Masanori
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Kazushi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Setsuo
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Takashi
authors.initials: T
authors.lastname: Asada
authors.forename: Milos D
authors.initials: MD
authors.lastname: Ikonomovic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000032:analysis*; D018797:Cell Cycle Proteins / Q000032:analysis*; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C107792:UBQLN1 protein, human
keywords: Alzheimer; Plic-1; amyloid; tau; ubiquilin