Price, Nathan D

There is considerable interest in harnessing innate immunity to treat Alzheimer’s disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity. Oligomeric and fibrillar Aβ modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling. Genetic analysis shows that rare protein coding variants in human TLR5 may be associated with a reduced risk of AD. Further, transcriptome analysis shows altered TLR gene expression in human AD. Collectively, our data suggest that TLR5 decoy receptor–based biologics represent a novel and safe Aβ-selective class of biotherapy in AD.

Abstract Summary Gap-filling is a necessary step to produce quality genome-scale metabolic reconstructions capable of flux-balance simulation. Most available gap-filling tools use an organism-agnostic approach, where reactions are selected from a database to fill gaps without consideration of the target organism. Conversely, our likelihood based gap-filling with probabilistic annotations selects candidate reactions based on a likelihood score derived specifically from the target organism’s genome. Here, we present two new implementations of probabilistic annotation and likelihood based gap-filling: a web service called ProbAnnoWeb, and a standalone python package called ProbAnnoPy. Availability and implementation Our tools are available as a web service with no installation needed (ProbAnnoWeb) at probannoweb.systemsbiology.net, and as a local python package implementation (ProbAnnoPy) at github.com/PriceLab/probannopy. Supplementary information Supplementary data are available at Bioinformatics online.

Abstract Introduction Comparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways. Methods We analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects. Results We identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD. Some of these associations were retained even after adjustments for brain cell population changes. These TCX myelination network structures were preserved in cerebellum but they were not differentially expressed in cerebellum between AD and PSP. Myelination networks were downregulated in both AD and PSP, when compared with control TCX samples. Discussion Downregulation of myelination networks may underlie both PSP and AD pathophysiology, but may be more pronounced in PSP. These data also highlight conservation of transcriptional networks across brain regions and the influence of cell type changes on these networks.

AbstractIntroductionWe hypothesized that common Alzheimer's disease (AD)‐associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression.MethodsExpression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis.ResultsA variant within a DNase hypersensitive site 5′ of TREM2, rs9357347‐C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10−3 and 4.6 × 10−2, respectively). Meta‐analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10−2 and 3.5 × 10−3, Bonferroni‐corrected P = 6.7 × 10−2 and 7.1 × 10−3, respectively).DiscussionOur findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome‐wide association study meta‐analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.

Summary A low‐diversity microbial community, dominated by the γ ‐proteobacterium H alomonas sulfidaeris , was detected in samples of warm saline formation porewater collected from the C ambrian Mt. S imon S andstone in the I llinois B asin of the N orth A merican M idcontinent (1.8 km/5872 ft burial depth, 50° C , pH 8, 181 bars pressure). These highly porous and permeable quartz arenite sandstones are directly analogous to reservoirs around the world targeted for large‐scale hydrocarbon extraction, as well as subsurface gas and carbon storage. A new downhole low‐contamination subsurface sampling probe was used to collect in situ formation water samples for microbial environmental metagenomic analyses. Multiple lines of evidence suggest that this H . sulfidaeris ‐dominated subsurface microbial community is indigenous and not derived from drilling mud microbial contamination. Data to support this includes V 1‐ V 3 pyrosequencing of formation water and drilling mud, as well as comparison with previously published microbial analyses of drilling muds in other sites. Metabolic pathway reconstruction, constrained by the geology, geochemistry and present‐day environmental conditions of the Mt . S imon S andstone, implies that H . sulfidaeris ‐dominated subsurface microbial community may utilize iron and nitrogen metabolisms and extensively recycle indigenous nutrients and substrates. The presence of aromatic compound metabolic pathways suggests this microbial community can readily adapt to and survive subsurface hydrocarbon migration.

AbstractThe biological role of vitamin D receptors (VDR), which are abundantly expressed in developing zebrafish (Danio rerio) as early as 48 h after fertilization, and before the development of a mineralized skeleton and mature intestine and kidney, is unknown. We probed the role of VDR in developing zebrafish biology by examining changes in expression of RNA by whole transcriptome shotgun sequencing (RNA-seq) in fish treated with picomolar concentrations of the VDR ligand and hormonal form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3)].We observed significant changes in RNAs of transcription factors, leptin, peptide hormones, and RNAs encoding proteins of fatty acid, amino acid, xenobiotic metabolism, receptor-activator of NFκB ligand (RANKL), and calcitonin-like ligand receptor pathways. Early highly restricted, and subsequent massive changes in more than 10% of expressed cellular RNA were observed. At days post fertilization (dpf) 2 [24 h 1α,25(OH)2D3-treatment], only four RNAs were differentially expressed (hormone vs. vehicle). On dpf 4 (72 h treatment), 77 RNAs; on dpf 6 (120 h treatment) 1039 RNAs; and on dpf 7 (144 h treatment), 2407 RNAs were differentially expressed in response to 1α,25(OH)2D3. Fewer RNAs (n = 481) were altered in dpf 7 larvae treated for 24 h with 1α,25(OH)2D3vs. those treated with hormone for 144 h. At dpf 7, in 1α,25(OH)2D3-treated larvae, pharyngeal cartilage was larger and mineralization was greater. Changes in expression of RNAs for transcription factors, peptide hormones, and RNAs encoding proteins integral to fatty acid, amino acid, leptin, calcitonin-like ligand receptor, RANKL, and xenobiotic metabolism pathways, demonstrate heretofore unrecognized mechanisms by which 1α,25(OH)2D3 functions in vivo in developing eukaryotes.