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 CX-5461 purchase 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

RAD001 research buy 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. The ubiquitin (Ub)–proteasome system is the major non-lysosomal proteolytic pathway in eukaryotes.[1] Ubiquilin-1 (also referred to as “protein linking integrin-associated protein to cytoskeleton 1”, or Plic-1) is a Ub-like (UBL) protein with functional domains

on its N-terminus (UB) and C-terminus (Ub-associated; UBA). Ubiquilin interacts with polyubiquitylated proteins through its UBA domain and with two subunits of the 19S proteasome through the UB domain.[2] UBL protein is observed in neurofibrillary tangles (NFT) in SPTLC1 Alzheimer’s disease (AD) brains,[3] facilitates presenilin synthesis[3] and modulates amyloid precursor protein trafficking and amyloid-beta (Aβ) secretion.[4] Previous studies reported that early in AD, UBL-1 protein levels decrease in the frontal cortex;[5] the status of UBL-1 protein levels in the hippocampus in patients with varying degrees of NFT pathology is unknown. In this study, we used immunohistochemical techniques to examine localization and alterations in UBL-1 protein in the hippocampus from cases at different stages of NFT pathology as classified by Braak and Braak.[6] Multiple-label immunofluorescent microscopy analyses examined the relationship of UBL with early and late NFT changes.