Brain region-specific amyloid plaque-associated myelin lipid loss, APOE deposition and disruption of the myelin sheath in familial Alzheimer's disease mice.

There is emerging evidence that amyloid beta (Aß) aggregates forming neuritic plaques lead to impairment of the lipid-rich myelin sheath and glia. In this study, we examined focal myelin lipid alterations and the disruption of the myelin sheath associated with amyloid plaques in a widely used familial Alzheimer's disease (AD) mouse model; 5xFAD. This AD mouse model has Aß42 peptide-rich plaque deposition in the brain parenchyma. Matrix-assisted laser desorption/ionization imaging mass spectrometry of coronal brain tissue sections revealed focal Aß plaque-associated depletion of multiple myelin-associated lipid species including sulfatides, galactosylceramides, and specific plasmalogen phopshatidylethanolamines in the hippocampus, cortex, and on the edges of corpus callosum. Certain phosphatidylcholines abundant in myelin were also depleted in amyloid plaques on the edges of corpus callosum. Further, lysophosphatidylethanolamines and lysophosphatidylcholines, implicated in neuroinflammation, were found to accumulate in amyloid plaques. Double staining of the consecutive sections with fluoromyelin and amyloid-specific antibody revealed amyloid plaque-associated myelin sheath disruption on the edges of the corpus callosum which is specifically correlated with plaque-associated myelin lipid loss only in this region. Further, apolipoprotein E, which is implicated in depletion of sulfatides in AD brain, is deposited in all the Aß plaques which suggest apolipoprotein E might mediate sulfatide depletion as a consequence of an immune response to Aß deposition. This high-spatial resolution matrix-assisted laser desorption/ionization imaging mass spectrometry study in combination with (immuno) fluorescence staining of 5xFAD mouse brain provides new understanding of morphological, molecular and immune signatures of Aß plaque pathology-associated myelin lipid loss and myelin degeneration in a brain region-specific manner. Read the Editorial Highlight for this article on page 7.

Hyperthermophilic flavin reductase from Sulfolobus solfataricus P2: Production and biochemical characterization.

Nicotinamide adenine dinucleotide phosphate (NAD(P)H)-flavin oxidoreductases (flavin reductases) catalyze the reduction of flavin by NAD(P)H and provide the reduced form of flavin mononucleotide (FMN) to flavin-dependent monooxygenases. Based on bioinformatics analysis, we identified a putative flavin reductase gene, sso2055, in the genome of hyperthermophilic archaeon Sulfolobus solfataricus P2, and further cloned this target sequence into an expression vector. The cloned flavin reductase (EC. 1.5.1.30) was purified to homogeneity and characterized further. The purified enzyme exists as a monomer of 17.8 kDa, free of chromogenic cofactors. Homology modeling revealed this enzyme as a TIM barrel, which is also supported by circular dichroism measurements revealing a beta-sheet rich content. The optimal pH for SSO2055 activity was pH 6.5 in phosphate buffer and the highest activity observed was at 120 °C within the measurable temperature. We showed that this enzyme can use FMN and flavin adenine dinucleotide (FAD) as a substrate to generate their reduced forms. The purified enzyme is predicted to be a potential flavin reductase of flavin-dependent monooxygenases that could be involved in the biodesulfurization process of S. solfataricus P2.

Decreased levels of cytokines implicate altered immune response in plasma of moderate-stage Alzheimer's disease patients.

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, increasing evidence suggests that the pathogenesis of the disease is associated with peripheral inflammation. Here, we aimed to determine plasma concentrations of multiple cytokines and chemokines from moderate-stage AD and age-matched controls. Changes in a total of 20 cytokines and chemokines in plasma of moderate-stage AD were evaluated by using quantitative microarray. Six of them, namely MCP-1, MIP-1a, MIP-1b, MMP-9, RANTES, and VEGF, were found to be significantly reduced in moderate-stage AD patients (n = 25) in comparison to age-matched and non-demented controls (n = 25). However, GM-CSF, GRO-α/ß/γ, IFN- γ, IL-1α, IL-1ß, IL-10, IL-12 p70, IL-13, IL-2, IL- 4, IL-5, IL-6, IL-8, and TNF-α showed no significant differences between the patient and control groups. On the contrary to previous early-stage AD studies that show increased plasma cytokine/chemokine levels, our results indicate that inflammatory plasma molecules are reduced in moderate-stage AD. This finding points out the reduced immune responsiveness, which is known to be directly correlated to the degree of AD.

Data for a proteomic analysis of p53-independent induction of apoptosis by bortezomib.

This data article contains data related to the research article entitled, "A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line" by Yerlikaya et al. [1]. The research article presented 2-DE and nLC-MS/MS based proteomic analysis of proteasome inhibitor bortezomib-induced changes in the expression of cellular proteins. The report showed that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24 h. In addition, the report demonstrated that Hsp70, the 26S proteasome non-ATPase regulatory subunit 14 and sequestosome 1 were increased at least 2 fold in p53-deficient 4T1 cells. The data here show for the first time the increased expressions of Card10, Dffb, Traf3 and Trp53bp2 in response to inhibition of the 26S proteasome. The information presented here also shows that both Traf1 and Xiap (a member of IAPs) are also downregulated simultaneously upon proteasomal inhibition. The increases in the level of Card10 and Trp53bp2 proteins were verified by Western blot analysis in response to varying concentrations of bortezomib for 24 h.