A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis

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

Опубликована: Апрель 24, 2025

Abstract Background Alzheimer’s disease (AD) is characterized by progressive amyloid beta (Aβ) deposition in the brain, with eventual widespread neurodegeneration. While cell-specific molecular signature of end-stage AD reasonably well through autopsy material, less known about pathways human brain involved earliest exposure to Aβ. Human model systems that not only replicate pathological features but also transcriptional landscape neurons, astrocytes and microglia are crucial for understanding mechanisms identifying novel therapeutic targets. Methods In this study, we used a 3D iPSC-derived neurosphere explore how resident their interplay modified chronic amyloidosis induced over 3–5 weeks supplementing media synthetic Aβ1 - 42 oligomers. Neurospheres under Aβ were grown or without investigate functional roles microglia. Neuronal activity oxidative stress monitored using genetically encoded indicators, including GCaMP6f roGFP1, respectively. Single nuclei RNA sequencing (snRNA-seq) was performed profile driven changes neurons astrocytes, providing comprehensive analysis cellular responses. Results Microglia efficiently phagocytosed inside neurospheres significantly reduced neurotoxicity, mitigating amyloidosis-induced neurodegeneration following different times The neuroprotective effects conferred presence associated unique gene expression profiles several AD-associated genes such as APOE . These findings reveal can directly alter AD. Conclusions Our culture system reveals may be essential responses pathogenesis. act key drivers Aβ-dependent suggesting critical regulating brain. This novel, characterized, vitro platform offers opportunities study modelling aspects tool will help identify new targets, accelerating transition from discovery clinical applications.

Язык: Английский

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Human Microglia Models for NeuroHIV

Viruses, Год журнала: 2025, Номер 17(5), С. 641 - 641

Опубликована: Апрель 29, 2025

Microglia are the primary target and reservoir of HIV infection in central nervous system (CNS), which contributes to HIV-associated neurocognitive disorder (HAND). However, studying microglia has been challenged by limited availability human microglial cells. To overcome this issue, investigators have developed various models for studies, including immortalized cell lines, latently infected clones, peripheral blood monocyte-derived (MMG), induced pluripotent stem (iPSC)-derived (iMg), microglia-containing cerebral organoids (MCOs) from iPSCs. Though these used many laboratories, published data about their expression specific markers entry receptors conflicting. In addition, there is information feasibility applicability as a suitable model acute and/or latent infection. This review provides concise summary currently models, with focus on suitability NeuroHIV research.

Язык: Английский

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Mutual interaction of neurons and astrocytes derived from iPSCs with APP V717L mutation developed the astrocytic phenotypes of Alzheimer’s disease

Inflammation and Regeneration, Год журнала: 2024, Номер 44(1)

Опубликована: Фев. 28, 2024

Abstract Background The development of induced pluripotent stem cells (iPSCs) technology has enabled human cellular disease modeling for inaccessible cell types, such as neural in the brain. However, many iPSC-derived models established to date typically involve only a single type. These monoculture are inadequate accurately simulating brain environment, where multiple types interact. limited type diversity hinders accurate recapitulation phenotypes resulting from interactions between different types. Therefore, our goal was create that include interacting better recapitulate phenotypes. Methods To establish co-culture model neurons and astrocytes, we individually astrocytes same iPSCs using novel differentiation methods, then co-cultured them. We evaluated effects on immunocytochemistry, immuno-electron microscopy, Ca 2+ imaging. also developed patient with familial Alzheimer's (AD) ( APP V717L mutation) investigate whether this would manifest not seen models. Results increased branching astrocyte processes, number GFAP-positive cells, neuronal activities, synapses, density presynaptic vesicles. In addition, microscopy confirmed formation tripartite synaptic structure model, inhibition glutamate transporters activity. Compared control iPSCs, AD astrogliosis-like phenotype, which observed astrocytes. Conclusions Co-culture enhanced morphological changes mimicking vivo condition both functional structures suggested mutual interaction cells. Furthermore, mutation expressed exhibited an astrocytic phenotype reminiscent pathology. results suggest is valuable tool neurodegenerative diseases.

Язык: Английский

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Aging phenotype in AD brain organoids: Track to success and challenges

Ageing Research Reviews, Год журнала: 2024, Номер 96, С. 102256 - 102256

Опубликована: Март 7, 2024

Alzheimer's disease (AD) poses a complex challenge, with abnormal protein accumulation in the brain causing memory loss and cognitive decline. Traditional models fall short AD research, prompting interest 3D organoids (BOs) from human stem cells. These findings hold promise for unveiling mechanisms of AD, especially relation to aging. However, an understanding aging impact remains elusive. BOs offer insight but face challenges. This review delves into role deciphering aging-related acknowledges limitations. Strategies enhance accurate modeling brains are suggested. Strengthened by molecular advancements, have potential uncover phenotype, advancing research.

Язык: Английский

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Schwann cell-secreted PGE2 promotes sensory neuron excitability during development

Cell, Год журнала: 2024, Номер 187(17), С. 4690 - 4712.e30

Опубликована: Авг. 1, 2024

Язык: Английский

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