iPSC-derived blood-brain barrier modeling reveals APOE isoform-dependent interactions with amyloid beta

Fluids and Barriers of the CNS, Год журнала: 2024, Номер 21(1)

Опубликована: Окт. 11, 2024

Abstract Background Three common isoforms of the apolipoprotein E ( APOE ) gene - APOE2 , APOE3 and APOE4 hold varying significance in Alzheimer’s Disease (AD) risk. The allele is strongest known genetic risk factor for late-onset (AD), its expression has been shown to correlate with increased central nervous system (CNS) amyloid deposition accelerated neurodegeneration. Conversely, associated reduced AD lower CNS burden. Recent clinical data have suggested that blood-brain barrier (BBB) leakage commonly observed among patients carriers. However, it remains unclear how different may impact AD-related pathologies at BBB. Methods To explore potential impacts genotypes on BBB properties interactions beta, we differentiated isogenic human induced pluripotent stem cell (iPSC) lines into both brain microvascular endothelial cell-like cells (BMEC-like cells) pericyte-like cells. We then compared effect BBB-related phenotypes. Statistical was determined via ANOVA Tukey’s post hoc testing as appropriate. Results Isogenic BMEC-like had similar trans-endothelial electrical resistance, tight junction integrity efflux transporter expression. recombinant protein significantly impeded “brain-to-blood” beta 1–40 (Aβ40) transport capabilities cells, suggesting a role diminished clearance. 1–42 (Aβ42) model. Furthermore, demonstrated APOE-mediated by dependent LRP1 p-glycoprotein pathways, mirroring vivo findings. Pericyte-like exhibited secretion levels across genotypes, yet showed heightened extracellular deposition, while displayed least an observation line vascular patients. Conclusions While genotype did not directly general BMEC or pericyte properties, exacerbated clearance model potentially protective increasing decreasing deposition. Our findings highlight iPSC-derived models can capture BBB, motivating further development such vitro modeling drug development.

Язык: Английский

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Cholesterol-mediated Lysosomal Dysfunction in APOE4 Astrocytes Promotes α-Synuclein Pathology in Human Brain Tissue

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 9, 2025

Summary The pathological hallmark of neurodegenerative disease is the aberrant post-translational modification and aggregation proteins leading to formation insoluble protein inclusions. Genetic factors like APOE4 are known increase prevalence severity tau, amyloid, α-Synuclein However, human brain largely inaccessible during this process, limiting our mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, cerebrovascular cells into a functional tissue (miBrain). Like brain, found pathogenic phosphorylation increased in miBrain. Combinatorial experiments revealed lipid-droplet astrocytes impairs degradation α-synuclein leads transformation seeds neuronal inclusions α-Synuclein. Collectively, study establishes robust for investigating highlights role cholesterol -mediated pathologies, opening therapeutic opportunities.

Язык: Английский

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MMP-9 inhibitor SB-3CT improves neurological outcomes in ischemic stroke mice by modulation of astrocytic lipid metabolism

Acta Pharmacologica Sinica, Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Язык: Английский

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Inflammation-induced lysosomal dysfunction in human iPSC-derived microglia is exacerbated by APOE 4/4 genotype

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Background. The ε4 isoform of apolipoprotein E (ApoE) is the most significant genetic risk factor for Alzheimer’s disease. Glial cells are main source ApoE in brain, and microglia, has been shown to impair mitochondrial metabolism uptake lipids Aβ42. However, whether alters autophagy or lysosomal activity microglia basal inflammatory conditions unknown. Methods. Altogether, microglia-like (iMGs) from eight APOE3/3 six APOE4/4 human induced pluripotent stem cell (iPSC) lines were used this study. responses iMGs Aβ42, LPS IFNγ studied by metabolomics, proteomics, functional assays. Results. Here, we demonstrate that with genotype exhibit reduced level pinocytosis an overall downregulation proteins compared iMGs. Inflammatory stimulation a combination Aβ42 PI3K/AKT/mTORC signaling pathway, increased pinocytosis, blocked autophagic flux, leading accumulation sequestosome 1 both Exposure furthermore caused membrane permeabilization, which was significantly stronger positively correlated secretion proinflammatory chemokine IL-8. Metabolomics analysis indicated dysregulation amino acid metabolism, primarily L-glutamine, Conclusions. Overall, our results suggest inflammation-induced metabolic reprogramming places lysosomes under substantial stress. Lysosomal stress more detrimental defects biogenesis.

Язык: Английский

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Inflammation-induced lysosomal dysfunction in human iPSC-derived microglia is exacerbated by APOE 4/4 genotype

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Июнь 2, 2025

Abstract Background The ε4 isoform of apolipoprotein E (ApoE) is the most significant genetic risk factor for Alzheimer’s disease. Glial cells are main source ApoE in brain, and microglia, has been shown to impair mitochondrial metabolism uptake lipids Aβ42. However, whether alters autophagy or lysosomal activity microglia basal inflammatory conditions unknown. Methods Altogether, microglia-like (iMGs) from eight APOE 3/3 six 4/4 human induced pluripotent stem cell (iPSC) lines were used this study. responses iMGs Aβ42, LPS IFNγ studied by metabolomics, proteomics, functional assays. Results Here, we demonstrate that with genotype exhibit reduced pinocytosis levels compared iMGs. Inflammatory stimulation a combination Aβ42 PI3K/AKT/mTORC signaling pathway, increased pinocytosis, blocked autophagic flux, leading accumulation sequestosome 1 (p62) both Exposure furthermore caused membrane permeabilization, which was significantly stronger positively correlated secretion proinflammatory chemokine IL-8. Metabolomics analysis indicated dysregulation amino acid metabolism, primarily L-glutamine, Conclusions Overall, our results suggest inflammation-induced metabolic reprogramming places lysosomes under substantial stress. Lysosomal stress more detrimental endo-lysosomal defects.

Язык: Английский

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Comparative gene regulatory networks modulatingAPOEexpression in microglia and astrocytes

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 20, 2024

Abstract Background Single-cell technologies have unveiled various transcriptional states in different brain cell types. Transcription factors (TFs) regulate the expression of related gene sets, thereby controlling these diverse states. Apolipoprotein E ( APOE ), a pivotal risk-modifying Alzheimer’s disease (AD), is expressed specific glial associated with AD. However, it still unknown whether upstream regulatory programs that modulate its are shared across types or to microglia and astrocytes. Methods We used pySCENIC construct state-specific networks (GRNs) for resting activated within astrocytes based on single-nucleus RNA sequencing data from AD patients’ cortices Knight ADRC-DIAN cohort. then identified replicating TF using ROSMAP sets genes co-regulated by clustering GRN target identifying differentially after virtual knockout TFs regulating . performed enrichment analyses evaluated their overlap found GWAS loci. Results an average 96 regulators each microglial astrocyte state. Our analysis CEBP, JUN, FOS, FOXO families as key expression. The steroid/thyroid hormone receptor families, including THR family, consistently regulated states, while CEBP JUN were also involved GWAS-associated PGRN , FCGR3A CTSH ABCA1 MARCKS CTSB SQSTM1 TSC22D4 FCER1G HLA genes) APOE. uncovered APOE-regulating linked circadian rhythm BHLHE40 DBP XBP1 CREM SREBF1 FOXO3 NR2F1 ). Conclusions findings reveal novel perspective regulation human brain. comprehensive cell-type-specific landscape revealing distinct mechanisms astrocytes, underscoring complexity regulation. -co-regulated might affect risk. Furthermore, our study uncovers potential link between disruption regulation, shedding new light pathogenesis

Язык: Английский

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Blockade of STARD3-mediated cholesterol transport alleviates diabetes-induced podocyte injury by reducing mitochondrial cholesterol accumulation

Life Sciences, Год журнала: 2024, Номер 349, С. 122722 - 122722

Опубликована: Май 15, 2024

Язык: Английский

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APOE4 increases energy metabolism in APOE-isogenic iPSC-derived neurons

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 3, 2024

Abstract The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer’s disease (AD). In contrast, APOE2 is known to lower AD while APOE3 defined as neutral. APOE plays a prominent role in bioenergetic homeostasis of brain, and early-stage metabolic changes have been detected brains patients. Although primarily expressed by astrocytes neurons also shown source APOE. However, little about differential three isoforms neuronal energy homeostasis. this study, we generated pure human (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE-knockout (KO) investigate isoform-specific effects on metabolism. We showed that endogenously produced enhanced mitochondrial ATP production iN but not corresponding iPS cell line. This effect neither correlated with expression levels fission fusion proteins, nor intracellular secreted APOE, which were similar cells. basal respiration APOE-KO strongly differed more closely resembled indicating gain-of-function mechanism rather than loss-of-function. Taken together, our findings isogenic reveal genotype-dependent neuron-specific regulation oxidative

Язык: Английский

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APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons

Cells, Год журнала: 2024, Номер 13(14), С. 1207 - 1207

Опубликована: Июль 17, 2024

The apolipoprotein E4 (

Язык: Английский

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Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia

Ageing and Neurodegenerative Diseases, Год журнала: 2024, Номер 4(2)

Опубликована: Май 6, 2024

Memory naturally declines as we age, but the rapid loss of memory can be distressing for people living with Alzheimer’s disease (AD). How memories are formed and retrieved in brain is not fully understood; it thought to require plasticity synapses connecting neurons a network engram cells. Plasticity may occur either through changes volume location molecules organelles within synapse, or gross structural synapses. do many mechanisms required learning memory, such concentrations cytoskeletal protein Microtubule-Associated Protein Tau, reduced glucose metabolism, sensitivities insulin. The biggest risk factor developing AD ageing, yet only few studies try reconcile natural decline functions see ageing dramatic impairment these pathways AD, Tau energy homeostasis by neurons. This review will therefore explain protein, during explore latest research that links processes neurodegeneration seen other Tauopathies. Understanding how dementia diverge offer an important underutilised avenue therapeutic interventions target metabolism both “healthy” disease.

Язык: Английский

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