Simultaneous imaging of redox states in dystrophic neurites and microglia at Aβ plaques indicate lysosome accumulation not microglia correlate with increased oxidative stress

Wendt, Stefan; Johnson, Sora; Weilinger, Nicholas L.; Groten, Christopher J.; Sorrentino, Stefano; Frew, Jonathan; Yang, Lucy; Choi, Hyun B.; MacVicar, Brian A.

doi:10.1016/j.redox.2022.102448

Cited by 7 publications

(8 citation statements)

References 77 publications

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“…Our hiNS did not develop necrotic regions, likely because they remain a smaller size, rarely exceeding a diameter of 500 μm. To monitor tissue health of hiNS, we transduced neurospheres with hSyn -roGFP1, a redox-sensitive green fluorescent protein that detects cellular oxidative stress associated with reactive oxygen species production and typically, necrosis 19,20 . As controls, DTT (5 mM) was used to fully reduce neurospheres and diamide (2 mM) to fully oxidize the tissue.…”

Section: Resultsmentioning

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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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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Section: Resultsmentioning

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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“…Figure 2f). Microglia are also seen pruning neuronal boutons or dendrites, which often contain phagosome-like vesicles—likely autophagosomes generated by oxidative stress(Talebi et al 2022; Wendt et al 2022).…”

Section: Resultsmentioning

confidence: 99%

“…Accumulation of brain metabolic waste can lead to inflammation and tissue damage, potentially causing dementia and other neurological disorders. While the current focus of brain-waste clearance is on the flow of cerebrospinal fluid (CSF) out of the brain via a lymphatic route(Rasmussen, Mestre, and Nedergaard 2022), recent research has highlighted the role of macrophages and microglia in waste removal(Drieu et al 2022; El Hajj et al 2019; Karam et al 2022; Kierdorf et al 2019; Spangenberg et al 2019; Wendt et al 2022). Macrophages and microglia are immune cells responsible for engulfing and eliminating cellular debris, pathogens, and other harmful substances, including metabolic waste.…”

Section: Introductionmentioning

confidence: 99%

Ultrastructure of the brain waste-clearance pathway

Grubb

2023

Preprint

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Efficient metabolic waste clearance is essential for optimal brain function. Waste accumulation can cause inflammation, tissue damage, and potentially lead to dementia and other neurological disorders. The primary waste exit route is debated, with evidence suggesting the lymphatic system or arachnoid villi/granulations as possible pathways. This study uses an ultrastructural dataset to emphasize the potential underestimation of macrophages and arachnoid villi/granulations in waste removal. The glymphatic system and neurovascular unit play crucial roles in this process, but their precise involvement is unclear. Based on brain surface ultrastructure analysis, waste clearance may occur through a transcellular route involving astrocytes to the perivascular space. Waste is then either phagocytosed by perivascular macrophages or directed to the subarachnoid space for meningeal macrophage phagocytosis. Evidence is provided that macrophages transport non-degradable waste in lysosomes to arachnoid villi for exocytosis into the villus lumen and venous system routing. Additionally, the study investigates fibroblast-macrophage interactions via primary cilia, potentially optimizing waste clearance. The role of astrocytes in brain water homeostasis and GFAP's potential significance in water filtration are also examined. This study offers valuable insights into waste clearance mechanisms in the brain, potentially aiding dementia understanding and treatment.

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“…When this lysosomal trafficking and maturation process is disrupted in AD pathology (Lie et al, 2022), it not only leads to cellular stress but also the accumulation of extracellular amyloid β (Aβ) (Lee et al, 2022). Additionally, accumulation of lysosomes around Aβ plaques is associated with increased oxidative stress (Wendt et al, 2022). Therefore, restoration of retrograde transport of endo-lysosomes may represent a therapeutic strategy to reduce not only dystrophic neurite pathology but also Aβ deposition and neurodegeneration during AD.…”

mentioning

confidence: 99%

“…Defects in the endosomal-lysosomal network can impact numerous homeostatic cellular processes including cell signaling, molecular trafficking, and clearance pathways (Nixon, 2017). Dysfunction of the endosomal-lysosomal system is also directly linked with Aβ deposition (Lee et al, 2022), oxidative stress (Wendt et al, 2022), and synaptic dysfunction (Adalbert et al, 2009). However, these dystrophic neurites are not entirely disrupted (Adalbert et al, 2009), suggesting that restoration of trafficking could still result in neuroprotective benefit.…”

mentioning

confidence: 99%

Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease

Odfalk,

Wickline,

Smith

et al. 2023

Hippocampus

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Dysfunction of the endosomal‐lysosomal network is a notable feature of Alzheimer's disease (AD) pathology. Dysfunctional endo‐lysosomal vacuoles accumulate in dystrophic neurites surrounding amyloid β (Aβ) plaques and may be involved in the pathogenesis and progression of Aβ aggregates. Trafficking and thus maturation of these dysfunctional vacuoles is disrupted in the vicinity of Aβ plaques. Transmembrane protein 55B (TMEM55B), also known as phosphatidylinositol‐4,5‐bisphosphate 4‐phosphatase 1 (PIP4P1) is an endo‐lysosomal membrane protein that is necessary for appropriate trafficking of endo‐lysosomes. The present study tested whether overexpression of TMEM55B in the hippocampus could prevent plaque‐associated axonal accumulation of dysfunctional endo‐lysosomes, reduce Aβ plaque load, and prevent hippocampal‐dependent learning and memory deficits in the 5XFAD mouse models of Aβ plaque pathology. Immunohistochemical analyses revealed a modest but significant reduction in the accumulation of endo‐lysosomes in dystrophic neurites surrounding Aβ plaques, but there was no change in hippocampal‐dependent memory or plaque load. Overall, these data indicate a potential role for TMEM55B in reducing endo‐lysosomal dysfunction during AD‐like Aβ pathology.

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Simultaneous imaging of redox states in dystrophic neurites and microglia at Aβ plaques indicate lysosome accumulation not microglia correlate with increased oxidative stress

Cited by 7 publications

References 77 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

Ultrastructure of the brain waste-clearance pathway

Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease

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