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• W4383341379 abstract "Abstract Background Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aβ peptides is the causative agent of AD pathology, but we still lack comprehensive understanding about the molecular mechanisms connecting Aβ peptides to neuronal dysfunctions in AD. In this work, we investigated the early effects of Aβ peptides accumulation on the functional properties and gene expression profiles of human-induced neurons (hiNs). Methods We exposed 6-weeks-old hiNs to low concentrations of cell-secreted Aβ oligomers or synthetic Aβ and performed time-lapse time microscopy to detect fast calcium transients as an indirect readout of neuronal electrical function. Next, we used single-nucleus RNA sequencing (snRNA-seq) to probe early Aβ-mediated gene expression alterations in hiNs and human-induced astrocytes (hiAs). Lastly, we leveraged snRNA-seq data to identify patterns of intercellular communication modulated by Aβ oligomers. Results We show that hiNs acutely exposed to low concentrations of both cell-secreted Aβ peptides or synthetic Aβ 1−42 exhibit alterations in the frequency of calcium transients suggestive of increased neuronal excitability. We also show that cell-secreted Aβ up-regulates the expression of several synaptic-related genes and down-regulates the expression of genes associated with metabolic stress mainly in glutamatergic neurons and to a lesser degree in GABAergic neurons and astrocytes. These neuronal alterations correlate with activation of SEMA5, EPHA and NECTIN signaling pathways, which are important regulators of synaptic plasticity. Conclusions Our findings indicate that slight elevations in Aβ concentrations are sufficient to elicit transcriptional changes in human neurons with long lasting consequences to neural network activity and suggest that at least part of the effects of Aβ on synapses might be mediated by semaphorin, ephrin and nectin signaling pathways." @default.
• W4383341379 created "2023-07-07" @default.
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• W4383341379 date "2023-07-06" @default.
• W4383341379 modified "2023-10-16" @default.
• W4383341379 title "Amyloid-beta peptides trigger premature functional and gene expression alterations in human-induced neurons" @default.
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• W4383341379 doi "https://doi.org/10.21203/rs.3.rs-3138106/v1" @default.
• W4383341379 hasPublicationYear "2023" @default.
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