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Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells
Adela Bernabeu-Zornoza1, Raquel Coronel1, Charlotte Palmer1
1Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain.
Abstract:
Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer's disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.
Insights
Amyloid-β 42 (Aβ42) peptides, both oligomers and fibrils, induce neural stem cell death and DNA damage. Oligomers most potently reduce proliferation and promote neurogenesis, offering insights into Alzheimer's disease mechanisms.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is linked to amyloid-β 42 peptide (Aβ42) accumulation in the brain.
- The precise role of different Aβ42 forms (oligomeric vs. fibrillary) in neural biology remains incompletely understood.
- Human neural stem cells (hNS1 cell line) provide a model to study Aβ42 effects on neuronal development.
Purpose of the Study:
- To compare the biological effects of oligomeric and fibrillary Aβ42 on differentiating human neural stem cells.
- To investigate Aβ42-induced changes in cell death, proliferation, and cell fate specification.
- To elucidate molecular mechanisms underlying Aβ42 toxicity in the context of Alzheimer's disease.
Main Methods:
- Utilized the hNS1 cell line for in vitro studies.
- Administered varying concentrations of oligomeric and fibrillary Aβ42 peptides.
- Assessed cell death (apoptosis), DNA damage, proliferative rates, and cell fate (gliogenesis and neurogenesis).
Main Results:
- High concentrations of both oligomeric and fibrillary Aβ42 induced apoptotic cell death and DNA damage, with fibrils showing a stronger effect.
- Both forms decreased cellular proliferation, but oligomers had a more significant impact.
- Both oligomers and fibrils promoted gliogenesis and neurogenesis, with oligomers exhibiting a more pronounced effect.
Conclusions:
- Aβ42 peptides, in both oligomeric and fibrillary forms, exert differential effects on neural stem cell biology.
- Oligomeric Aβ42 appears to have a greater impact on proliferation and cell fate specification compared to fibrillary Aβ42.
- Findings contribute to understanding AD pathogenesis and developing neural stem cell-based therapeutic strategies for AD.
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