There were no statistically significant differences in demographics between the three Braak stage groups, although the Braak stage 0-I-II (non-AD) group trended toward younger age (P = 0.013 by Kruskal-Wallis,

no differences were detected with Dunn’s multiple comparison test). UBL immunoreactivity had distinct patterns in the three Braak stage groups MI-503 ic50 (described below), and localization was almost exclusively neuronal in all groups, with only in 2/11 cases (one Braak stage VI, one Braak stage IV with family history of AD) exhibiting UBL immunoreactivity in cells with the morphological appearance of microglia and oligodendrocytes, and located throughout the gray and white matter, respectively (not shown). In Braak stage 0-I-II cases (NFT absent or confined to the PF-01367338 chemical structure entorhinal cortex), UBL immunoreactivity was observed in the neuropil in the stratum pyramidale

of the Ammon’s horn (CA) and molecular layer of the dentate gyrus (DG). UBL immunoreactivity was also detected in neuronal soma, dendrites and in the nucleoplasm in hippocampal neurons, including pyramidal and multipolar neurons in the CA fields, and DG granular neurons. In the majority of neurons, UBL immunoreactivity intensity was higher in the nucleoplasm compared to the cytoplasm (Fig. 1; Table 2). UBL immunoreactivity in the nucleoplasm appeared punctuate/vesicular (Fig. 1 inset a; Fig. 4A) and was most prominent in the CA2/3 field (Table 2). In Braak stage III-IV cases (NFT involving the entorhinal cortex and hippocampus but not neocortex), UBL immunoreactivity in the neuropil was reduced in the CA1 and CA2/3 regions, and was unchanged in the CA4 and DG, compared to Braak stage 0-I-II cases. The majority of CA1 neurons exhibited reduced cytoplasmic and nucleoplasmic labelling; however, a subset of CA1 pyramidal neurons had prominent UBL immunoreactivity in the nucleoplasm (Fig. 1B). The intensity of UBL immunoreactivity in the nucleoplasm increased markedly in the

majority of CA2/3 pyramidal Tacrolimus (FK506) neurons, CA4 multipolar neurons and DG granular neurons (Figs 1E, 2H,K; Table 2). We also observed UBL immunoreactivity in fibers in the CA2/3 radiatum/moleculare and DG molecular layer in three of the Braak stage III-IV cases (Braak III: 1; Braak IV: 2; not shown). In Braak stage V-VI cases, UBL immunoreactivity was less intense in the CA1 field, both in the neuropil and in pyramidal neurons, except those with the morphological appearance of extracellular NFT (eNFT), where UBL immunoreactivity was prominent (Fig. 1C. inset c). In contrast, UBL immunoreactivity in neuropil and neuronal cytoplasm in CA2/3, CA4 and DG was similar to the pattern observed in Braak stage III–IV cases, albeit with a less prominent increase in nucleoplasmic UBL immunoreactivity (Fig. 1F,I,L; Table 2). Analysis of UBL immunoreactivity optical density confirmed a significant increase (P < 0.