Single cell transcriptome analysis of the THY-Tau22 mouse model of Alzheimer's disease reveals sex-dependent dysregulations

peer reviewedAlzheimer's disease (AD) progression and pathology show pronounced sex differences, but the factors driving these remain poorly understood. To gain insights into early AD-associated molecular changes and their sex-dependence for tau pathology in the cortex, we performed single-cell RNA-seq in the THY-Tau22 AD mouse model. By examining cell type-specific and cell type-agnostic AD-related gene activity changes and their sex-dimorphism for individual genes, pathways and cellular sub-networks, we identified both statistically significant alterations and interpreted the upstream mechanisms controlling them. Our results confirm several significant sex-dependent alterations in gene activity in the THY-Tau22 model mice compared to controls, with more pronounced alterations in females. Both changes shared across multiple cell types and cell type-specific changes were observed. The differential genes showed significant over-representation of known AD-relevant processes, such as pathways associated with neuronal differentiation, programmed cell death and inflammatory responses. Regulatory network analysis of these genes revealed upstream regulators that modulate many of the downstream targets with sex-dependent changes. Most key regulators have been previously implicated in AD, such as Egr1, Klf4, Chchd2, complement system genes, and myelin-associated glycoproteins. Comparing with similar data from the Tg2576 AD mouse model and human AD patients, we identified multiple genes with consistent, cell type-specific and sex-dependent alterations across all three datasets. These shared changes were particularly evident in the expression of myelin-associated genes such as Mbp and Plp1 in oligodendrocytes. In summary, we observed significant cell type-specific transcriptomic changes in the THY-Tau22 mouse model, with a strong over-representation of known AD-associated genes and processes. These include both sex-neutral and sex-specific patterns, characterized by consistent shifts in upstream master regulators and downstream target genes. Collectively, these findings provide insights into mechanisms influencing sex-specific susceptibility to AD and reveal key regulatory proteins that could be targeted for developing treatments addressing sex-dependent AD pathology.Validating Digital Biomarkers For Better Personalized Treatment Of Parkinson's Disease3. Good health and well-bein

Isolated Amyloid-β(1–42) Protofibrils, But Not Isolated Fibrils, Are Robust Stimulators of Microglia

[Image: see text] Senile plaques composed of amyloid-β protein (Aβ) are an unshakable feature of the Alzheimer’s disease (AD) brain. Although there is significant debate on the role of the plaques in AD progression, there is little disagreement on their role in stimulating a robust inflammatory response within the context of the disease. Significant inflammatory markers such as activated microglia and cytokines are observed almost exclusively surrounding the plaques. However, recent evidence suggests that the plaque exterior may contain a measurable level of soluble Aβ aggregates. The observations that microglia activation in vivo is selectively stimulated by distinct Aβ deposits led us to examine what specific form of Aβ is the most effective proinflammatory mediator in vitro. We report here that soluble prefibrillar species of Aβ(1–42) were better than fibrils at inducing microglial tumor necrosis factor α (TNFα) production in either BV-2 and primary murine microglia. Reconstitution of Aβ(1–42) in NaOH followed by dilution into F-12 media and isolation with size exclusion chromatography (SEC) revealed classic curvilinear β-sheet protofibrils 100 nm in length. The protofibrils, but not monomers, markedly activated BV-2 microglia. Comparisons were also made between freshly isolated protofibrils and Aβ(1–42) fibrils prepared from SEC-purified monomer. Surprisingly, while isolated fibrils had a much higher level of thioflavin T fluorescence per mole, they were not effective at stimulating either primary or BV-2 murine microglia compared to protofibrils. Furthermore, SEC-isolated Aβ(1–40) protofibrils exhibited significantly less activity than concentration-matched Aβ(1–42). This report is the first to demonstrate microglial activation by SEC-purified protofibrils, and the overall findings indicate that small, soluble Aβ(1–42) protofibrils induce much greater microglial activation than mature insoluble fibrils

Porous metal–organic-framework nanoscale carriers as a potential platform for drug delivery and imaging

In the domain of health, one important challenge is the efficient delivery of drugs in the body using non-toxic nanocarriers. Most of the existing carrier materials show poor drug loading (usually less than 5 wt% of the transported drug versus the carrier material) and/or rapid release of the proportion of the drug that is simply adsorbed (or anchored) at the external surface of the nanocarrier. In this context, porous hybrid solids, with the ability to tune their structures and porosities for better drug interactions and high loadings, are well suited to serve as nanocarriers for delivery and imaging applications. Here we show that specific non-toxic porous iron(III)-based metal–organic frameworks with engineered cores and surfaces, aswell as imaging properties, function as superior nanocarriers for efficient controlled delivery of challenging antitumoural and retroviral drugs (that is, busulfan, azidothymidine triphosphate, doxorubicin or cidofovir) against cancer and AIDS. In addition to their high loadings, they also potentially associate therapeutics and diagnostics, thus opening the way for theranostics, or personalized patient treatments

Expression and signaling of Formyl-Petide Receptors in the brain

The human formyl-peptide receptor (FPR) and its variants FPRL1 and FPRL2 belong to the G-protein coupled seven transmembrane receptor (GPCR) family sensitive to pertussis toxin. FPR and FPRL1 were first detected in phagocytic leukocytes, and FPRL2 was found in monocytes and in dendritic cells. The three receptors were subsequently identified in other cell types or tissues, including neuronal cells and brain, where FPR and FPRL1 play a key role in angiogenesis, cell proliferation, protection against and cell death, as well as in neuroendocrine functions. Binding of different agonists to FPRs triggers several signaling pathways, activates NFkB and STAT3 transcriptional factors and induces the accumulation of the CDK inhibitors p21waf1/cip1, p16INK4 and p27kip1. Signaling molecules, such as ERKs, JNK, PKC, p38MAPK, PLC and PLD are involved in these intracellular cascades. In this article we briefly review FPRs expression and signaling in neuronal cells

One-day prevalence of asymptomatic carriage of toxigenic and non-toxigenic Clostridioides difficile in 10 French hospitals

International audienceBackground: Asymptomatic faecal carriage of Clostridioides difficile has been widely evaluated, but its prevalence across a wide range of clinical departments and related risk factors are not well described. The objectives of the PORTADIFF study were to evaluate the prevalence and identifying risk factors leading to asymptomatic carriage of both toxigenic and non-toxigenic C. difficile.Methods: The PORTADIFF study was a 1-day prevalence study carried out in 10 different French hospitals. Adult patients, who agreed to participate, were included in this study and provided a fresh stool sample. C. difficile strains isolated from carriage were characterized by polymerase chain reaction (PCR) detection of tcdA, tcdB, cdtA and cdtB, and PCR ribotyping.Results: In total, 721 patients were included in this study. The median age was 73 years (range 18-101 years) and the male/female ratio was 1.06. C. difficile (either toxigenic or non-toxigenic strains) was isolated from 79 (11%) patients; 42 (5.8%) strains were toxigenic. The prevalence rates of asymptomatic carriage ranged from 5% on surgical wards to 19% on long-term care wards. The main risk factors associated with asymptomatic carriage were antibiotic treatment within the preceding 3 months (81.8% vs 53.7%; P<0.01), hospitalization within the preceding 2 months (55.8% vs 33%; P<0.01), cumulative duration of hospital stay before study inclusion (mean 50.1 vs 34.5 days; P<0.047), and hospitalization on a ward with high global incidence of C. difficile infection.Conclusion: Eleven percent of hospitalized patients were asymptomatic carriers of toxigenic or non-toxigenic C. difficile, and may constitute a potential reservoir of C. difficile strains