Citations

Abstract The apolipoprotein E ε4 ( APOE4 ) allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet the mechanistic underpinnings by which it alters human microglial function remain poorly understood. Here, we utilize CRISPR/Cas9-engineered isogenic human induced pluripotent stem cell-derived microglia-like cells (iMGs) expressing APOE3 or APOE4 to systematically interrogate genotype-dependent effects on microglial proteomes and their secreted extracellular vesicles (EVs) under basal and fibrillar amyloid-β (fAβ)-challenged conditions. Quantitative proteomics revealed that APOE4 iMGs exhibit downregulated RNA processing, impaired phagocytosis, and exacerbated pro-inflammatory signaling, particularly upon fAβ exposure. Functionally, APOE4 iMGs demonstrated increased NF-κB activation, enhanced neuronal apoptosis and tau pathology in 2D and 3D co-culture systems. Interestingly, APOE4 iMGs released greater amount of EVs enriched in proteasomal components over APOE3 iMG. Integrated proteomic analyses further highlighted APOE4 -specific selective packaging of EV cargo linked to neuron-glia communication, inflammatory signaling, and proteostasis dysregulation, suggesting a potent, non-cell-autonomous mechanism driving neuronal damage. Consistently, these APOE4 iMGEVs were preferentially internalized by neurons, leading to disrupted neuronal proteostasis, impaired neuronal firing, and increased tau phosphorylation, particularly under pathological stress. Notably, pharmacologic inhibition of NF-κB in APOE4 iMGs reduced EV cargo-loading of proteasomal molecules and mitigated iMGEV-driven neuronal dysfunction and tau pathology. These findings establish a mechanistic link between APOE4 , dysregulated microglial homeostasis, and microglial EV-mediated propagation of proteostatic dysfunction and neurodegeneration, advancing our understanding of how APOE4 contributes to AD pathogenesis.

Background and Goals: Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with cirrhosis and ascites, with additional risks posed by multidrug-resistant organisms (MDRO). This real-world study evaluated clinical outcomes in patients with SBP and the impact of MDRO. Methods: This study identified US adults with SBP receiving guideline-recommended treatment with antibiotics and albumin from January 2012 to June 2022. Antibiotic utilization trends, health care resource utilization, and clinical outcomes [in-hospital and ICU mortality and hospital and ICU length of stay (LOS)] were assessed and stratified by MDRO status. Results: A total of 10,956 patients with 12,570 encounters were identified. Median age was 57.0 years (IQR=49.0 to 65.0), and 62.4% were male; suspected MDRO infections occurred in 15% of encounters. Third-generation cephalosporins were used in 71.6%, 49.2% had acute kidney injury, and 20.0% and 7.2% had hepatorenal syndrome and hepatic encephalopathy, respectively. Median hospital LOS was 7.2 days (IQR=4.3 to 12.9), with 17.7% in-hospital mortality. ICU care was required in 14.5% of encounters, with a median ICU LOS of 3.6 days (IQR=1.7 to 6.7) and ICU mortality of 29.7%. MDRO infections were associated with increased in-hospital mortality (OR=2.24, P <0.001) and decreased hazard of hospital discharge (ie, prolonged LOS; HR=0.43, P <0.001). Receiving albumin within 24 hours of admission was associated with a 72% higher hazard of hospital discharge (ie, shorter LOS; HR=1.72, P <0.001). Conclusion: This study highlights the clinical and resource burden of SBP, emphasizing the impact of MDRO infections and the importance of timely albumin administration concordant with clinical guidelines.

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

Peroxisome-proliferator–activated receptor delta (PPARδ) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPARδ agonists, KD3010 and T3D-959, in two established ALS/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43Q331K transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9–10 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43Q331K mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement—particularly for T3D-959—neither PPARδ agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPARδ activation without therapeutic benefit. Together, these findings demonstrate that PPARδ agonism is insufficient to modify disease progression in these ALS/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

Background: Cirrhosis and cirrhosis-related deaths have risen in the United States in recent years. Ascites is a common complication, often requiring large-volume paracentesis (LVP). The American Association for the Study of Liver Diseases (AASLD) recommends the administration of albumin in conjunction with LVP to prevent further complications of cirrhosis. Emerging research in cirrhosis care reveals significant variations in outcomes among different demographics. Therefore, we assessed the use of guideline-adherent albumin and outcomes in U.S. patients undergoing LVPs, particularly at the intersection of race, ethnicity, socioeconomic disparities, and cirrhosis. Methods: This retrospective study utilized Cerner Real World Data to identify adults with cirrhosis and ascites undergoing LVP between January 2016 and June 2022. We assessed albumin utilization patterns across racial and ethnic groups and payor types, and their overall impact on acute kidney injury (AKI)-related hospitalization using an adjusted generalized linear model (aGLM). Results: We identified 736 patients: 301 in the LVP + albumin group and 435 in the LVP-only group. Despite clinical recommendations, only 41% undergoing LVPs received albumin. White patients and commercially insured patients received albumin at higher rates (p=0.042 and p=0.009, respectively). The overall rate of AKI-related admissions within the 30-day post-procedure period was 26%. However, patients who received albumin during LVP had a 36% lower risk of short-term AKI-related hospitalization (OR: 0.64; p=0.03). Conclusions: These findings indicate a potential for broader albumin utilization in U.S. patients with refractory ascites undergoing repeated LVPs to reduce AKI-related admissions.