The degree of astrocyte activation is predictive of the incubation time to prion disease

Acta Neuropathologica Communications, Год журнала: 2021, Номер 9(1)

Опубликована: Май 12, 2021

In neurodegenerative diseases including Alzheimer's, Parkinson's and prion diseases, astrocytes acquire disease-associated reactive phenotypes. With growing appreciation of their role in chronic neurodegeneration, the questions whether lose ability to perform homeostatic functions states phenotypes are neurotoxic or neuroprotective remain unsettled. The current work examined region-specific changes expression genes, which report on astrocyte physiological states, C57Black/6J mice challenged with four strains via two inoculation routes. Unexpectedly, strong reverse correlation between incubation time degree activation along disturbance functional pathways was observed. animal groups most severe response showed rapid disease progression. tightly intertwined global transformation state, characterized by disturbances multiple gene sets responsible for normal producing a neurotoxic, phenotype as net result. exhibited universal signature regardless strain. suggests that contribute faster progression perhaps even drive pathogenesis.

Язык: Английский

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Single-cell spatial proteomic imaging for human neuropathology

Acta Neuropathologica Communications, Год журнала: 2022, Номер 10(1)

Опубликована: Ноя. 4, 2022

Abstract Neurodegenerative disorders are characterized by phenotypic changes and hallmark proteopathies. Quantifying these in archival human brain tissues remains indispensable for validating animal models understanding disease mechanisms. We present a framework nanometer-scale, spatial proteomics with multiplex ion beam imaging (MIBI) capturing neuropathological features. MIBI facilitated simultaneous, quantitative of 36 proteins on hippocampus from individuals spanning cognitively normal to dementia. Customized analysis strategies identified cell types proteopathies the across stages Alzheimer’s (AD) neuropathologic change. show microglia-pathologic tau interactions hippocampal CA1 subfield AD Data driven, sample independent creation proteomic regions persistent neurons pathologic neighborhoods expressing mitochondrial protein MFN2, regardless cognitive status, suggesting survival advantage. Our study revealed unique insights multiplexed data-driven approaches serves broadly as methodology neuropathology. Teaser Multiplex Ion Imaging enables deep phenotyping neuropathology-associated cellular

Язык: Английский

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Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Янв. 3, 2023

Abstract Background Astrocytes are crucial for maintaining brain homeostasis and synaptic function, but also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Our previous data demonstrate that astrocytes ingest large amounts aggregated amyloid-beta (Aβ), then store, rather than degrade ingested material, which leads severe cellular stress. However, involvement pathological in AD-related dysfunction remains be elucidated. Methods In this study, we aimed investigate how intracellular deposits Aβ affect their interplay with neurons, focusing on neuronal function viability. For purpose, human induced pluripotent stem cell (hiPSC)-derived were exposed sonicated Αβ 42 fibrils. The direct indirect effects Αβ-exposed hiPSC-derived neurons analyzed by performing astrocyte–neuron co-cultures as well additions conditioned media or extracellular vesicles pure cultures. Results Electrophysiological recordings revealed significantly decreased frequency excitatory post-synaptic currents co-cultured Aβ-exposed astrocytes, while from had opposite effect resulted hyperactivation synapses. Clearly, factors secreted control, not benefited wellbeing Moreover, reactive led an elevated clearance dead cells co-cultures. Conclusions Taken together, our results inclusions state ability support function.

Язык: Английский

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Long-term effects of amyloid-beta deposits in human iPSC-derived astrocytes

Molecular and Cellular Neuroscience, Год журнала: 2023, Номер 125, С. 103839 - 103839

Опубликована: Март 11, 2023

Growing evidence indicates that astrocytes are tightly connected to Alzheimer's disease (AD) pathogenesis. However, the way in which participate AD initiation and progression remains be clarified. Our previous data show engulf large amounts of aggregated amyloid-beta (Aβ) but unable successfully degrade material. In this study, we aimed evaluate how intracellular Aβ-accumulation affects over time. For purpose, human induced pluripotent cell (hiPSC)-derived were exposed sonicated Aβ-fibrils then cultured further for one week or ten weeks Aβ-free medium. Cells from both time points analyzed lysosomal proteins astrocyte reactivity markers media screened inflammatory cytokines. addition, overall health cytoplasmic organelles was investigated by immunocytochemistry electron microscopy. demonstrate long-term retained frequent Aβ-inclusions enclosed within LAMP1-positive sustained associated with reactivity. Furthermore, resulted endoplasmic reticulum mitochondrial swelling, increased secretion cytokine CCL2/MCP-1 formation pathological lipid structures. Taken together, our results provide valuable information Aβ-deposits affect astrocytes, thereby contribute understanding role progression.

Язык: Английский

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BMAL1 in Astrocytes: A Protective Role in Alzheimer’s and Parkinson’s Disease

Neuroglia, Год журнала: 2025, Номер 6(1), С. 1 - 1

Опубликована: Янв. 2, 2025

Astrocyte activation is a critical aspect of brain health and disease, the central circadian clock protein BMAL1 has emerged as regulator astrogliosis inflammatory gene expression. Bmal1 deletion in astrocytes reprograms endolysosomal transcriptional pathways, inducing endocytosis, lysosomal degradation, autophagic activity. This regulation proteostasis by implicates proteins neurodegenerative diseases. Studies suggest that astrocyte complex process with diverse phenotypes beyond classic markers such GFAP, exhibiting neurotoxic neuroprotective effects. Deletion shown protective effects models Alzheimer’s disease (AD) Parkinson’s (PD), influencing Aβ accumulation α-syn pathology, respectively, through state mitigates tauopathy possibly induction chaperone BAG3. These findings crucial regulating astrocytic function neuroprotection review explores relationship between dysfunction development/progression AD PD. Furthermore, it recapitulates most recent on manipulating its potential astrocytes.

Язык: Английский

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