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The mechanisms underpinning neuronal death in Alzheimer's disease (AD) remain unclear. Caccamo and colleagues show that necroptosis contributes to neurodegeneration in AD. Blocking necroptosis reduced neuronal loss in a mouse model of AD, suggesting that necroptosis might be a therapeutic target in AD. Alzheimer's disease (AD) is characterized by severe neuronal loss; however, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We found that necroptosis was activated in postmortem human AD brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores. In addition, we found that the set of genes regulated by RIPK1 overlapped significantly with multiple independent AD transcriptomic signatures, indicating that RIPK1 activity could explain a substantial portion of transcriptomic changes in AD. Furthermore, we observed that lowering necroptosis activation reduced cell loss in a mouse model of AD. We anticipate that our findings will spur a new area of research in the AD field focused on developing new therapeutic strategies aimed at blocking its activation.

Background Herbicides are environmental contaminants that have gained much attention due to the potential hazards they pose to human health. Glyphosate, the active ingredient in many commercial herbicides, is the most heavily applied herbicide worldwide. The recent rise in glyphosate application to corn and soy crops correlates positively with increased death rates due to Alzheimer’s disease and other neurodegenerative disorders. Glyphosate has been shown to cross the blood–brain barrier in in vitro models, but has yet to be verified in vivo. Additionally, reports have shown that glyphosate exposure increases pro-inflammatory cytokines in blood plasma, particularly TNFα. Methods Here, we examined whether glyphosate infiltrates the brain and elevates TNFα levels in 4-month-old C57BL/6J mice. Mice received either 125, 250, or 500 mg/kg/day of glyphosate, or a vehicle via oral gavage for 14 days. Urine, plasma, and brain samples were collected on the final day of dosing for analysis via UPLC–MS and ELISAs. Primary cortical neurons were derived from amyloidogenic APP/PS1 pups to evaluate in vitro changes in Aβ 40-42 burden and cytotoxicity. RNA sequencing was performed on C57BL/6J brain samples to determine changes in the transcriptome. Results Our analysis revealed that glyphosate infiltrated the brain in a dose-dependent manner and upregulated TNFα in both plasma and brain tissue post-exposure. Notably, glyphosate measures correlated positively with TNFα levels. Glyphosate exposure in APP/PS1 primary cortical neurons increases levels of soluble Aβ 40-42 and cytotoxicity. RNAseq revealed over 200 differentially expressed genes in a dose-dependent manner and cell-type-specific deconvolution analysis showed enrichment of key biological processes in oligodendrocytes including myelination, axon ensheathment, glial cell development, and oligodendrocyte development. Conclusions Collectively, these results show for the first time that glyphosate infiltrates the brain, elevates both the expression of TNFα and soluble Aβ, and disrupts the transcriptome in a dose-dependent manner, suggesting that exposure to this herbicide may have detrimental outcomes regarding the health of the general population.

Factors governing the development of liver fibrosis in nonalcoholic steatohepatitis (NASH) are only partially understood. We recently identified adipocyte enhancer binding protein 1 (AEBP1) as a member of a core set of dysregulated fibrosis-specific genes in human NASH. Here we sought to investigate the relationship between AEBP1 and hepatic fibrosis. We confirmed that hepatic AEBP1 expression is elevated in fibrosis compared to lobular inflammation, steatosis, and normal liver, and increases with worsening fibrosis in NASH patients. AEBP1 expression was upregulated 5.8-fold in activated hepatic stellate cells and downregulated during chemical and contact induction of biological quiescence. In LX-2 and HepG2 cells treated with high glucose (25 mM), AEBP1 expression increased over 7-fold compared to normal glucose conditions. In response to treatment with either fructose or palmitate, AEBP1 expression in primary human hepatocytes increased 2.4-fold or 9.6-fold, but was upregulated 55.8-fold in the presence of fructose and palmitate together. AEBP1 knockdown resulted in decreased expression of nine genes previously identified to be part of a predicted AEBP1-associated NASH co-regulatory network and confirmed to be upregulated in fibrotic tissue. We identified binding sites for two miRNAs known to be downregulated in NASH fibrosis, miR-372-3p and miR-373-3p in the AEBP1 3' untranslated region. Both miRNAs functionally interacted with AEBP1 to regulate its expression. These findings indicate a novel AEBP1-mediated pathway in the pathogenesis of hepatic fibrosis in NASH.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by immune-mediated demyelination and axonal injury. Recent works have highlighted the critical role of myeloid cells in MS, contributing to both neurodegeneration and repair. FK506-binding protein 5 (FKBP5), a co-chaperone of the glucocorticoid receptor and regulator of stress responses, has been implicated in MS pathology, yet its mechanistic role remains poorly understood. Here, we show that FKBP5 expression is elevated in monocytes and dendritic cells from the cerebrospinal fluid of people with MS and enriched in microglial nodules. Additionally, we show that genetic ablation or pharmacological inhibition of Fkbp5 in microglia and macrophages enhances myelin uptake and degradation via phagolysosomal pathways and attenuates interferon-gamma (IFNg)-induced transcriptional programs. In the experimental autoimmune encephalomyelitis (EAE) model of MS, systemic treatment with the selective FKBP5 inhibitor SAFit2 reduced immune cell infiltration, dampened microglial activation, and suppressed IFNg signaling, resulting in improved clinical outcomes. Taken together, our data identify FKBP5 as a critical mediator of myeloid cell-driven neuroinflammation, and a promising therapeutic target in MS.

Alzheimer's disease (AD), the most common form of dementia, has treatments that slow but do not stop cognitive decline. Additional treatments are based on its pathogenic mechanisms are needed. Evidence has long highlighted oxidative stress and impaired glucose metabolism as crucial factors in AD pathogenesis. Therefore, in this study we aimed to find key AD pathogenic pathways combining genes involved in oxidative stress and glucose metabolism as well as potential small-molecule therapeutic agents. Using autopsy brain RNA sequencing data (GSE125583) derived from the Arizona Study of Aging and Brain and Body Donation Program, AD-related genes were identified via differential gene expression, pathway and coexpression analysis. Oxidative stress and glucose metabolism genes were correlated to pinpoint module genes. GSE173955 was used an independent dataset was used for validation, conducting molecular docking, assessing hub genes for AD, and integrating machine learning approaches. We identified 13,982 differentially expressed genes (DEGs) in AD patients. Through WGCNA coexpression analysis, 1,068 genes were linked to AD-specific modules. Pearson's correlation analysis highlighted 99 genes involved in oxidative stress and glucose metabolism. Overlap analysis of DEGs, module genes, and these metabolic genes revealed 21 key overlapping targets. PPI network and receiving operating curve (ROC) curve analyses then identified AKT1 and PPARGC1A as diagnostic hub genes for AD. Machine learning-based virtual screening of small molecules identified various inhibitors and enhancers with drug-like potential targeting AKT1 (upregulated) and PPARGC1A (downregulated), respectively. Among others, the Random Forest model was the most reliable for predicting molecular activity. Molecular docking further validated the binding affinities of these small molecules (inhibitors/enhancers) to AKT1 and PPARGC1A. This study identified AKT1 and PPARGC1A as potential therapeutic targets in AD. We discovered drug candidates with strong binding affinities, offering new avenues for effective AD treatment strategies.

Achaete-scute homolog 1 gene (ASCL1) is a gene classifier for the proneural (PN) transcriptional subgroup of glioblastoma (GBM) that has a relevant role in the neuronal-like differentiation of GBM cancer stem cells (CSCs) through the activation of a PN gene signature. Besides prototypical ASCL1 PN target genes, the molecular effectors mediating ASCL1 function in regulating GBM differentiation and, most relevantly, subgroup specification are currently unknown. Here we report that ASCL1 not only promotes the acquisition of a PN phenotype in CSCs by inducing a glial-to-neuronal lineage switch but also concomitantly represses mesenchymal (MES) features by directly downregulating the expression of N-Myc downstream-regulated gene 1 (NDRG1), which we propose as a novel gene classifier of MES GBMs. Increasing the expression of ASCL1 in PN CSCs results in suppression of self-renewal, promotion of differentiation and, most significantly, decrease in tumorigenesis, which is also reproduced by NDRG1 silencing. Conversely, both abrogation of ASCL1 expression in PN CSCs and enforcement of NDRG1 expression in either PN or MES CSCs induce proneural-to-mesenchymal transition (PMT) and enhanced mesenchymal features. Surprisingly, ASCL1 overexpression in MES CSCs increases malignant features and gives rise to a neuroendocrine-like secretory phenotype. Altogether, our results propose that the fine interplay between ASCL1 and its target NDRG1 might serve as potential subgroup-specific targetable vulnerability in GBM; enhancing ASCL1 expression in PN GBMs might reduce tumorigenesis, whereas repressing NDRG1 expression might be actionable to hamper the malignancy of GBM belonging to the MES subgroup.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), pose significant risks of severe fibrosis, cirrhosis, and hepatocellular carcinoma. Despite their widespread prevalence, the molecular mechanisms underlying the development and progression of these common chronic hepatic conditions are not fully understood. Here, we conducted the most extensive meta-analysis of hepatic gene expression datasets from liver biopsy samples to date, integrating 10 RNA-sequencing and microarray datasets (1,058 samples). Using a random-effects meta-analysis model, we compared over 12,000 shared genes across datasets. We identified 685 genes differentially expressed in MASLD versus normal liver, 1,870 in MASH versus normal liver, and 3,284 in MASLD versus MASH. Integrating these results with genome-wide association studies and coexpression networks, we identified two functionally relevant, validated coexpression modules mainly driven by SMOC2, ITGBL1, LOXL1, MGP, SOD3, and TAT, HGD, SLC25A15, respectively, the latter not previously associated with MASLD and MASH. Our findings provide a comprehensive and robust analysis of hepatic gene expression alterations associated with MASLD and MASH and identify novel key drivers of MASLD progression.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is common among midlife women. Circulating extracellular vesicles (EVs) carry bioactive cargo that may mediate or reflect disease processes, but their role in hepatic steatosis in postmenopausal women remains unexplored. Methods We conducted liquid chromatography data-independent acquisition–mass spectrometry on serum-derived EVs from 275 postmenopausal women enrolled in the Michigan site of the Study of Women’s Health Across the Nation (MI-SWAN). Participants were grouped by hepatic steatosis status ( n  = 75), assessed via standardized ultrasound at the 2010 follow-up visit. Fasting serum samples were processed using size exclusion chromatography to isolate EVs. Differential EV protein abundance was evaluated by ANCOVA, adjusting for ethnicity and diabetes status, and applying Benjamini–Hochberg correction. Gene Set Enrichment Analysis (GSEA) was performed to identify enriched biological pathways. Results Among 469 detected EV proteins, 60 differed by hepatic steatosis status ( p  < 0.05), with two proteins remaining significant after multiple testing correction: complement C4A (C4A) and afamin (AFM). GSEA indicated enrichment in lipid metabolism and innate immune activation pathways. Subgroup analyses revealed racial and disease severity-specific differences in EV protein profiles. In Black women ( n  = 172), AFM, C4A, and APOA1 were significantly elevated, while in White participants ( n  = 103), no proteins reached significance, although AFM displayed a nonsignificant trend toward higher abundance. In participants with severe hepatic steatosis ( n  = 43), subgroup analysis showed increased COL18A1, AFM, PRG4, and INHBE and decreased C4A and APOA1. INHBE was the only protein consistently elevated across all three subgroups, whereas others showed subgroup-specific enrichment, such as immunoglobulins in Black women and complement or coagulation proteins in White participants and those with severe steatosis. Analysis of hepatic transcriptomic datasets demonstrated consistently higher INHBE expression across the MASLD spectrum, including metabolic dysfunction-associated steatohepatitis (MASH), while AFM expression was significantly higher in the MASH vs. steatosis comparison. Conclusions This study demonstrates that circulating EV proteomes differ by hepatic steatosis status in postmenopausal women. While exploratory, candidate EV proteins such as INHBE and AFM merit validation as biomarkers and potential contributors to MASLD in this high-risk population.

Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein with several immunosuppressive and pro-tumor functions. The role of Galectin-3 in cancer stem-like cells (CSCs) is poorly investigated. Here, we show that prostate CSCs also colonizing prostate-draining lymph nodes of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice overexpress Gal-3. Gal-3 contributes to prostate CSC-mediated immune suppression because either Gal-3 silencing in CSCs, or co-culture of CSCs and T cells in the presence of the Gal-3 inhibitor N-Acetyl-D-lactosamine rescued T cell proliferation. N-Acetyl-D-lactosamine also rescued the proliferation of T cells in prostate-draining lymph nodes of TRAMP mice affected by prostate intraepithelial neoplasia. Additionally, Gal-3 impacted prostate CSC tumorigenic and metastatic potential , as Gal-3 silencing in prostate CSCs reduced both primary tumor growth and secondary invasion. Gal-3 was also found expressed in more differentiated prostate cancer cells, but with different intracellular distribution as compared to CSCs, which suggests different functions of Gal-3 in the two cell populations. In fact, the prevalent nuclear and cytoplasmic distribution of Gal-3 in prostate CSCs made them less susceptible to apoptosis, when compared to more differentiated prostate cancer cells, in which Gal-3 was predominantly intra-cytoplasmic. Finally, we found Gal-3 expressed in human and mouse prostate intraepithelial neoplasia lesions and in metastatic lymph nodes. All together, these findings identify Gal-3 as a key molecule and a potential therapeutic target already in the early phases of prostate cancer progression and metastasis.