hiPSC-derived GRN-deficient astrocytes delay spiking activity of developing neurons

Lee, Christopher; Frew, Jonathan; Weilinger, Nicholas L.; Wendt, Stefan; Cai, Wei; Sorrentino, Stefano; Wu, Xiujuan; MacVicar, Brian A.; Willerth, Stephanie M.

doi:10.1016/j.nbd.2023.106124

Cited by 4 publications

(2 citation statements)

References 29 publications

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“…Peripheral blood was drawn and hiPSCs were generated from erythroid progenitor cells. The cell line has been used and characterized by our laboratory in the past 90,91 .…”

Section: Methodsmentioning

confidence: 99%

“…Peripheral blood was drawn and hiPSCs were generated from erythroid progenitor cells. The cell line has been used and characterized by our laboratory in the past 90,91 . hiPSCs were grown on Matrigel (BD Biosciences, Franklin Lakes, USA) coated 6-well plates in mTeSR TM Plus (STEMCELL Technologies, Vancouver, Canada).…”

Section: Generation Of Human Ipscs and Induction Of Npcsmentioning

confidence: 99%

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Microglia-astrocyte interplay mitigates Aβ toxicity in a novel human 3D neurosphere model of Alzheimer's Disease

Wendt,

Lin,

Ebert

et al. 2024

Preprint

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Microgliosis and astrogliosis characteristically occur at Aβ plaques in the brains of Alzheimer's disease (AD) patients although the impact of gliosis in AD is poorly understood. We studied the impact of Aβ-induced gliosis using human induced pluripotent stem cell (hiPSC)-derived 3D neurospheres (hiNS), containing only astrocytes and neurons versus hiNS with the addition of iPSC-derived microglia (hiMG). Applying Aβ to hiNS containing only astrocytes and neurons triggered pathological features of AD including plaque-like aggregates, reactive astrocytes, oxidative stress, neuronal dysfunction and cell death. In contrast, when hiMG were combined with hiNS, infiltrating hiMG effectively phagocytose Aβ and facilitate neuroprotection. Our findings further support a pivotal role for microglia in modulating astrocyte Aβ responses by inducing AD-associated gene expression in astrocytes, including the upregulation of APOE, crucial for Aβ clearance. This model, highlighting the neuroprotective potential of microglia-astrocyte interactions, offers a novel platform for exploring AD mechanisms and novel therapeutic strategies.

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“…Peripheral blood was drawn and hiPSCs were generated from erythroid progenitor cells. The cell line has been used and characterized by our laboratory in the past 90,91 .…”

Section: Methodsmentioning

confidence: 99%

Section: Generation Of Human Ipscs and Induction Of Npcsmentioning

confidence: 99%

Microglia-astrocyte interplay mitigates Aβ toxicity in a novel human 3D neurosphere model of Alzheimer's Disease

Wendt,

Lin,

Ebert

et al. 2024

Preprint

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WDR49‐Positive Astrocytes Mark Severity of Neurodegeneration in Frontotemporal Lobar Degeneration and Alzheimer's Disease

Rajicic,

Giannini,

Gerrits

et al. 2024

Glia

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A subpopulation of astrocytes expressing WD Repeat Domain 49 (WDR49) was recently identified in frontotemporal lobar degeneration (FTLD) with GRN pathogenic variants. This is the first study to investigate their expression and relation to pathology in other FTLD subtypes and Alzheimer's disease (AD). In a postmortem cohort of TDP‐43 proteinopathies (12 GRN, 11 C9orf72, 9 sporadic TDP‐43), tauopathies (13 MAPT, 8 sporadic tau), 10 AD, and four controls, immunohistochemistry and immunofluorescence were performed for WDR49 and pathological inclusions on frontal, temporal, and occipital cortical sections. WDR49‐positive cell counts (adjusted per mm2) were examined and related to digitally quantified percentage areas of TDP‐43/tau pathology and semiquantitative scores of neurodegeneration. Quantitative colocalization analysis of WDR49 and pathological inclusions was done. WDR49‐positive astrocytes were present across FTLD subtypes and AD in the brain parenchyma and (peri‐)vascular space, with distinct morphological patterns, and were particularly enriched in gray matter. In controls, sporadic WDR49‐positive cells were found enveloping vessels. WDR49‐positive astrocytes were most abundant in the frontal cortex (FC) of GRN cases and temporal cortex in GRN, AD, and sporadic primary tauopathy. In the occipital cortex, only a few cells were found across groups. WDR49‐positive astrocyte counts positively correlated with the severity of neurodegeneration and TDP‐43 pathology but not tauopathy. Furthermore, in frontotemporal cortices, WDR49 partly colocalized with TDP‐43 (14%–21%) and tau (31%–45%). In conclusion, WDR49 is a marker for a subset of astrocytes with different morphologies across FTLD and AD, reflecting the severity of neurodegeneration. These astrocytes may become activated in neurodegeneration in response to pathological damage and migrate from the vessel wall to the parenchyma.

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How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?

Cheng,

Cook,

Talbot

et al. 2024

Neurotox Res

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Excitotoxicity linked either to environmental causes (pesticide and cyanotoxin exposure), excitatory neurotransmitter imbalance, or to intrinsic neuronal hyperexcitability, is a pathological mechanism central to neurodegeneration in amyotrophic lateral sclerosis (ALS). Investigation of excitotoxic mechanisms using in vitro and in vivo animal models has been central to understanding ALS mechanisms of disease. In particular, advances in induced pluripotent stem cell (iPSC) technologies now provide human cell-based models that are readily amenable to environmental and network-based excitotoxic manipulations. The cell-type specific differentiation of iPSC, combined with approaches to modelling excitotoxicity that include editing of disease-associated gene variants, chemogenetics, and environmental risk-associated exposures make iPSC primed to examine gene-environment interactions and disease-associated excitotoxic mechanisms. Critical to this is knowledge of which neurotransmitter receptor subunits are expressed by iPSC-derived neuronal cultures being studied, how their activity responds to antagonists and agonists of these receptors, and how to interpret data derived from multi-parameter electrophysiological recordings. This review explores how iPSC-based studies have contributed to our understanding of ALS-linked excitotoxicity and highlights novel approaches to inducing excitotoxicity in iPSC-derived neurons to further our understanding of its pathological pathways.

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hiPSC-derived GRN-deficient astrocytes delay spiking activity of developing neurons

Cited by 4 publications

References 29 publications

Microglia-astrocyte interplay mitigates Aβ toxicity in a novel human 3D neurosphere model of Alzheimer's Disease

Microglia-astrocyte interplay mitigates Aβ toxicity in a novel human 3D neurosphere model of Alzheimer's Disease

WDR49‐Positive Astrocytes Mark Severity of Neurodegeneration in Frontotemporal Lobar Degeneration and Alzheimer's Disease

How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?

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