Single-Cell Detection of Secreted Aβ and sAPPα from Human IPSC-Derived Neurons and Astrocytes

Liao, Mei-Chen; Muratore, Christina; Gierahn, Todd M.; Sullivan, Sarah E.; Srikanth, Priya; Jager, Philip L. De; Love, J. Christopher; Young‐Pearse, Tracy L.

doi:10.1523/jneurosci.2735-15.2016

Cited by 88 publications

(78 citation statements)

References 38 publications

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“…Han and colleagues 114 extended this approach to monitor the kinetic expression of four cytokines over 17 hours from thousands of activated T cells, demonstrating that cytokine release kinetics can predict T cell effector phenotype. Similar work by Liao et al 115 in human neurons and astrocytes derived from induced pluripotent stem cells isolated from healthy donors and people with familial Alzheimer disease enabled quantification of secreted amyloid-β and soluble amyloid precursor protein-α, demonstrating unexpected secretion patterns across single cells. In each instance, further improvements in detection efficiency, target number and throughput would extend the utility of these approaches.…”

Section: Microfluidic Devices For the Omicssupporting

confidence: 52%

Scaling by shrinking: empowering single-cell 'omics' with microfluidic devices

2017

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Recent advances in cellular profiling have demonstrated substantial heterogeneity in the behaviour of cells once deemed ‘identical’, challenging fundamental notions of cell ‘type’ and ‘state’. Not surprisingly, these findings have elicited substantial interest in deeply characterizing the diversity, interrelationships and plasticity among cellular phenotypes. To explore these questions, experimental platforms are needed that can extensively and controllably profile many individual cells. Here, microfluidic structures—whether valve-, droplet- or nanowell-based—have an important role because they can facilitate easy capture and processing of single cells and their components, reducing labour and costs relative to conventional plate-based methods while also improving consistency. In this article, we review the current state-of-the-art methodologies with respect to microfluidics for mammalian single-cell ‘omics’ and discuss challenges and future opportunities.

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Section: Microfluidic Devices For the Omicssupporting

confidence: 52%

Scaling by shrinking: empowering single-cell 'omics' with microfluidic devices

2017

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“…To date, several research groups have reported the usage of iPSCs in AD modeling, which provide a proof-of-principle for modeling patient-specific AD pathology in human brain-like environment [25–30, 37–42, 48, 49, 52, 53]. These patient-derived AD neurons were mainly generated from FAD patients but also a few from sAD patients.…”

Section: Recapitulating Aβ Pathology In Human Ipsc-derived Neuronsmentioning

confidence: 99%

3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”

Choi

Kim

Quinti

et al. 2016

Mol Neurodegeneration

109

122

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Alzheimer’s disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including β-amyloid (Aβ) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Aβ deposition and Aβ-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Aβ and p-tau pathologies in human neural cell cultures, as compared the standard two-dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs.

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“…BACE‐1 stability and function also are influenced by other neural proteins, including ubiquilin‐1 and septin‐8 (17, 18). A greater understanding of the relative role of these astrocyte pathways in generation of Ab peptides in the brain has come from recent analyses of human induced pluripotent stem cell‐ derived neural cells (19). With these methods, astrocytes were shown to secrete high levels of Ab peptides, and astrocyte‐like cells were prominently represented among the highest producers of Ab peptides.…”

mentioning

confidence: 99%

Cargo proteins of plasma astrocyte‐derived exosomes in Alzheimer's disease

et al. 2016

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Efficient intercellular transfer of RNAs, proteins, and lipids as protected exosomal cargo has been demonstrated in the CNS, but distinct physiologic and pathologic roles have not been well defined for this pathway. The capacity to isolate immunochemically human plasma neuron-derived exosomes (NDEs), containing neuron-specific cargo, has permitted characterization of CNS-derived exosomes in living humans. Constituents of the amyloid β-peptide (Aβ)42-generating system now are examined in 2 distinct sets of human neural cells by quantification in astrocyte-derived exosomes (ADEs) and NDEs, enriched separately from plasmas of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD) and matched cognitively normal controls. ADE levels of β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), γ-secretase, soluble Aβ42, soluble amyloid precursor protein (sAPP)β, sAPPα, glial-derived neurotrophic factor (GDNF), P-T181-tau, and P-S396-tau were significantly (3- to 20-fold) higher than levels in NDEs for patients and controls. BACE-1 levels also were a mean of 7-fold higher in ADEs than in NDEs from cultured rat type-specific neural cells. Levels of BACE-1 and sAPPβ were significantly higher and of GDNF significantly lower in ADEs of patients with AD than in those of controls, but not significantly different in patients with FTD than in controls. Abundant proteins of the Aβ42 peptide-generating system in ADEs may sustain levels in neurons. ADE cargo proteins may be useful for studies of mechanisms of cellular interactions and effects of BACE-1 inhibitors in AD.-Goetzl, E. J., Mustapic, M., Kapogiannis, D., Eitan, E., Lobach, I. V., Goetzl, L., Schwartz, J. B., Miller, B. L. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease.

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Single-Cell Detection of Secreted Aβ and sAPPα from Human IPSC-Derived Neurons and Astrocytes

Cited by 88 publications

References 38 publications

Scaling by shrinking: empowering single-cell 'omics' with microfluidic devices

Scaling by shrinking: empowering single-cell 'omics' with microfluidic devices

3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”

Cargo proteins of plasma astrocyte‐derived exosomes in Alzheimer's disease

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