Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer’s disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APP/PS1 transgenic mice. Our findings reveal that deacetylation of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0269-2) contains supplementary material, which is available to authorized users.
Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify ADspecific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids andThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Neuroinflammation occurs early in Alzheimer’s disease (AD). The initial stage of AD is related to glial dysfunction, which contributes to impairment of Aβ clearance and disruption of synaptic connection. CEBPβ, a member of the CCAAT-enhancer-binding protein (CEBP) family, modulates the expression of inflammation-associated genes, and its expression is elevated in brains undergoing degeneration and injured brains. However, the mechanism underlying CEBPβ-mediated chronic inflammation in AD is unclear. In this study, we observed that increases in the levels of nuclear CEBPβ facilitated the interaction of CEBPβ with the NFκB p65 subunit, increasing the transcription of proinflammatory cytokines in the APP/PS1 mouse brain. Oral administration of nanocarrier-packaged carnosic acid (CA) reduced the aberrant activation of microglia and astrocytes and diminished mature IL-1β, TNFα and IL-6 production in the APP/PS1 mouse brain. CA administration reduced β-amyloid (Aβ) deposition and ameliorated cognitive impairment in APP/PS1 mice. We observed that CA blocked the interaction of CEBPβ with NFκB p65, and chromatin immunoprecipitation revealed that CA reduced the transcription of the NFκB target genes TNFα and IL-6. We confirmed that CA alleviated inflammatory mediator-induced neuronal degeneration and reduced Aβ secretion by inhibiting the CEBPβ-NFκB signalling pathway in vitro. Sulfobutyl ether-beta-cyclodextrin (SBEβCD) was used as the encapsulation agent for the CA-loaded nanocarrier to overcome the poor water solubility and enhance the brain bioavailability of CA. The CA nanoparticles (NPs) had no obvious toxicity. We demonstrated a feasible SBEβCD-based nanodelivery system targeting the brain. Our data provide experimental evidence that CA-loaded NPs are potential therapeutic agents for AD treatment.
Fat deposition in muscle includes intramuscular fat (IMF) and intermuscular fat. IMF content is an index of pork quality; however, because IMF content is difficult to measure in vivo in young animals, conventional breeding for IMF content is difficult to carry out. The mechanism and progression of animal fat deposition is not well understood, and there are currently no effective control methods. In this study, using Laiwu and large white pigs as the research subjects and RNA sequencing technology, we analyzed the genetic mechanism of animal fat deposition in pigs. Specifically, we analyzed the features of lncRNAs and their potential target genes. We obtained 464 million clean reads, from which 907 lncRNAs were identified. The
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analysis identified target genes, including genes that were upregulated (286) and downregulated (621) in the fatty and lean pigs. ENSSSCG00000008692_ADD1, ENSSSCG00000023124_ADD1 and ENSSSCG00000005918_DGAT1 were validated as target genes of the lncRNAs and were shown to be closely related to fat deposition. These results provide a basis for studying the different metabolic lncRNA expression of IMF deposition. In addition, as the valuable model animal to study the mechanisms of obesity, pigs may represent a new avenue for studying human obesity.
Many nature reserves are established to protect the habitat needs of particular endangered species of interest but their effectiveness for protecting other species is questionable. In this study, this effectiveness was evaluated in a nature reserve network located in the Qinling Mountains, Shaanxi Province, China. The network of reserves was established mainly for the conservation of the giant panda, a species considered as a surrogate for the conservation of many other endangered species in the region. The habitat suitability of nine protected species, including the giant panda, was modeled by using Maximum Entropy (MAXENT) and their spatial congruence was analyzed. Habitat suitability of these species was also overlapped with nature reserve boundaries and their management zones (i.e., core, buffer and experimental zones). Results show that in general the habitat of the giant panda constitutes a reasonable surrogate of the habitat of other protected species, and giant panda reserves protect a relatively high proportion of the habitat of other protected species. Therefore, giant panda habitat conservation also allows the conservation of the habitat of other protected species in the region. However, a large area of suitable habitat was excluded from the nature reserve network. In addition, four species exhibited a low proportion of highly suitable habitat inside the core zones of nature reserves. It suggests that a high proportion of suitable habitat of protected species not targeted for conservation is located in the experimental and buffer zones, thus, is being affected by human activities. To increase their conservation effectiveness, nature reserves and their management zones need to be re-examined in order to include suitable habitat of more endangered species. The procedures described in this study can be easily implemented for the conservation of many endangered species not only in China but in many other parts of the world. Keywords: giant panda; habitat suitability; Maximum Entropy (MAXENT); nature reserve network; surrogate species Citation: Xu Weihua, Viña Andrés, Qi Zengxiang, Ouyang Zhiyun, Liu Jianguo, Liu Wei, Wan Hui, 2014. Evaluating conservation effectiveness of nature reserves established for surrogate species: Case of a giant panda nature reserve in Qinling Mountains, China.
Increased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated F-FDG PET could improve microadenoma detection.
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