Background: Conservative site-specific recombination is responsible for the resolution of cointegrates which result during the transposition of class II transposable elements. Resolution is catalysed by a transposonencoded recombinase, resolvase, that belongs to a large family of recombinases, including DNA invertases. Resolvases and the related invertases are likely to employ similar reaction mechanisms during recombination. There are important differences, however. Resolvases require two accessory DNA binding sites within each of the two directly repeated recombination sites. Invertases instead need a host factor, Fis, and an enhancer type DNA sequence, in addition to two inversely orientated recombination sites.

BackgroundNeurofibrillary tangles are dynamic entities with a lifespan encompassing three maturity levels: intracellular pretangles, intracellular mature tangles, and extracellular ghost tangles. Proteins are suggested to be differentially expressed throughout the tangle lifespan; however, past studies may be limited by spatial expression or number of proteins investigated. We sought to assess differences in protein expression across the tangle lifespan using GeoMxTM Digital Spatial Profiler (DSP) by NanoString, a new technology allowing for spatially derived multiplex investigation.MethodWe used DSP to measure protein expression in hippocampi from Alzheimer’s disease (n=6) and nondemented controls (n=2) using the “Human Neural Cell Profiling Core” and “Alzheimer’s Pathology” module. Regions of interest (ROIs) were classified by the major tangle maturity level recognized by a primary fluorescent conjugated tau antibody. Protein expression was normalized to the geomean of the three housekeeping genes. The tau‐positive segment was specifically analyzed for comparisons. ANOVA was used for group‐wise comparisons and t‐test using the Benjamini‐Yekutieli adjustment for multiple tests was used for pair‐wise comparisons.ResultAs expected, cytoskeletal (e.g., MAP2, Tau) and neuronal (e.g., NeuN) markers generally decreased through the neurofibrillary tangle lifespan (Figure). Markers profiled as neurodegenerative (e.g., amyloid‐β1‐42, APOE, APP) generally increased through tangle maturity levels, except for TDP‐43 which decreased. Interestingly, there was no significant difference in ubiquitin expression. Astrocytic GFAP and S100B expression was significantly increased through each maturity level. Expression of microglial‐specific markers P2RY12 and TMEM119 was significantly elevated in ghost tangles compared to mature tangles. Additional microglial/macrophage markers including Iba‐1 and CD68 were generally increased as neurofibrillary tangles matured. Interestingly, APOE expression remained low in pretangles and mature tangles before dramatically increasing in ghost tangles (Figure).ConclusionOur findings suggest that proteins are differentially expressed throughout the tangle lifespan and the majority followed a monotonically directed pattern. Non‐monotonically directed protein patterns may reflect the death of the neuron during the ghost tangle maturity level. Future studies will test the hypothesis that the microenvironment of the hippocampus is altered with increasing vulnerability to tangle pathology.

Design, Synthesis and Diversification of Natural Product-Inspired Hydantoin--Fused Tetrahydroazepino Indoles. -(BARVE, I. J.; DALVI, P. B.; THIKEKAR, T. U.; CHANDA, K.; LIU, Y.-L.; FANG, C.-P.; LIU, C.-C.; SUN*, C.-M.; RSC Adv. 5 (2015) 89, 73169-73179, http://dx.

Apolipoprotein E (APOE) is a lipid transporter involved in neural cholesterol metabolism. Highly expressed in astrocytes and microglia, APOE4, one of the three isoforms of the transporter, is a strong genetic risk factor for Alzheimer’s disease, while APOE3 is considered moderate risk and APOE2 protective. Despite recent advances in Alzheimer’s disease research, the exact mechanism by which APOE4 influences the progression of the disease has yet to be determined. One hallmark pathological feature of Alzheimer’s disease is the accumulation of hyperphosphorylated tau protein in the brain. To investigate the role of APOE isoform expression in the accumulation of hyperphosphorylated tau protein, a microglia‐specific cre‐ recombinase‐mediated APOE inducible mouse model was used. Phosphorylated‐tau accumulation, microglia activation, and neurodegeneration of the hippocampus and piriform cortex upon specific expression of APOE3 were quantified. APOE3 expressing mice had exacerbated neurodegeneration and tau accumulation in the hippocampus. Additionally, it appeared that APOE3 expressing mice had increased microglial activation. Thus, APOE expression may be involved in the activation of microglia in Alzheimer’s disease, eliciting an overactive immune response that accelerates disease progression.