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APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4 -related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4 -related phenotypes and suggests APOE4 -related degenerative pathways contributing to AD pathogenesis. APOE4 is a strong genetic risk factor for late-onset Alzheimer’s disease. Here, the authors show that APOE4 is associated with AD features in hiPSCs-derived cerebral organoids. Isogenic conversion of APOE4 to APOE3 attenuates the AD-associated phenotype.

The rapid growth of China’s electric vehicle (EV) market has led to a peak in end-of-life (EOL) power batteries, yet the recycling sector remains dominated by informal operations. This paper incorporates the formal and informal recycling participation behaviours of EV owners into the framework of evolutionary games, systematically examines the mechanism by which governmental incentive and disincentive mechanisms influence the evolutionary stability of each party, and constructs a tripartite evolutionary game model involving the government, recycling enterprises, and EV owners. Numerical simulation experiments conducted using PyCharm 2.3 provide an in-depth exploration of the strategic evolutionary trajectories of each participating agent. The findings indicate that (1) the stable strategy for the game-theoretic system of EOL power battery recycling is government non-regulation, recycling enterprises adopting formal recycling practices, and EV owners participating in formal recycling; (2) strengthening penalties against recycling enterprises will accelerate their transition towards formal recycling strategies, while increasing incentive levels can significantly enhance the steady-state probability of firms opting for formal recycling; (3) government subsidies for EV owners encourage both EV owners and recycling enterprises to adopt formal recycling, with recycling enterprises shifting first. This study enriches the application of evolutionary game theory in the field of EOL power battery recycling and further provides guidance for the healthy development of the recycling industry.

Microglial involvement in Alzheimer’s disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E ( APOE ) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk. Liu and colleagues find differential effects of microglial apoE isoforms on brain function and microglial responses. ApoE3 enhances microglial responses, promoting brain function and reducing amyloid deposition and associated neurotoxicity, while the Alzheimer’s disease-associated apoE4 results in lipid droplet accumulation and impaired microglial responses, which are critical for limiting the development of amyloid pathology.

Consumer satisfaction critically determines the operational sustainability of fresh food e-commerce platforms, yet integrated investigations combining multi-source data remain scarce. This study develops a theory–data fusion framework to identify key satisfaction drivers in China’s fresh e-commerce sector. Utilizing Python-based crawlers, we extracted 1252 online reviews of Aksu apples from a certain fresh produce e-commerce platform alongside 509 validated questionnaires. Through systematic literature synthesis, three core dimensions—perceived value (price–performance balance), platform experience (interface usability), and perceived quality (freshness assurance)—were operationalized into measurable indicators. The final structural equation model reveals that perceived value, platform experience, and perceived quality all have significant positive impacts on consumer satisfaction. This study pioneers a methodological paradigm integrating computational text mining (Octopus Collector + SPSS Pro) with traditional psychometric scales, achieving superior model fit (RMSEA = 0.023, CFI = 0.981). These findings empower platforms to implement a precision strategy. The validated framework provides a theoretical basis for omnichannel consumer research while addressing the data-source bias prevalent in prior studies.

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to AppNL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.

APOE4 is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.

Mounting evidence highlights the crucial role of aging in the pathogenesis of Alzheimer's disease (AD). We have previously explored human apoE-targeted replacement mice across different ages and identified distinct molecular pathways driven by aging. However, the specific contribution of different brain cell types to the gene modules underlying these pathways remained elusive. To bridge this knowledge gap, we employed a computational deconvolution approach to examine cell-type-specific gene expression profiles in major brain cell types, including astrocytes (AS), microglia (MG), oligodendroglia (OG), neurons (NEU), and vascular cells (VC). Our findings revealed that immune module genes were predominantly expressed in MG, OG, and VC. The lipid metabolism module genes were primarily expressed in AS, MG, and OG. The mitochondria module genes showed prominent expression in VC, and the synapse module genes were primarily expressed in NEU and VC. Furthermore, we identified intra- and inter-cell-type interactions among these module genes and validated their aging-associated expression changes using published single cell studies. Our study dissected bulk brain transcriptomics data at the cellular level, providing a closer examination of the cell-type contributions to the molecular pathways driven by aging.

Background Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, and premature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC (iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs . Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.

Background The apolipoprotein E ( APOE ) gene is the strongest genetic risk factor for Alzheimer’s disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. Methods We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE -deficient ( APOE −/− ) iPSC line. To elucidate the cell-type-specific effects of APOE deficiency in the cerebral organoids, we performed scRNA-seq in the parental and APOE −/− cerebral organoids at Day 90. Results We show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single-cell RNA sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the eukaryotic initiation factor 2 (EIF2) signaling pathway as these events were alleviated by the treatment of an integrated stress response inhibitor (ISRIB). APOE deletion also leads to activation of the Wnt/β-catenin signaling pathway with concomitant decrease of secreted frizzled-related protein 1 ( SFRP1 ) expression in glia cells. Importantly, the critical role of apoE in cell-type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3 . Conclusions Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4 -related pathogenic mechanisms.