Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells

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.

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer’s disease inPrnpmutant mice and in the P301S transgenic tauopathy mice model

“…We were able to determine this in vitro showing a relevant decrease of TUJ1 immunostaining after treatment with sarkosyl-insoluble fractions of P301S +/− or AD, and in vivo . The negative effect of amyloid fibrils, prefibrils vs oligomeric forms in cell survival has been described for several amyloids including Aβ [15], insulin fibers [6], lysozyme fibrils [66] see also ([24] for additional examples and review) using several protocols and experimental approaches. In fact, although a clear consensus is still elusive, brain-derived sarkosyl-insoluble fractions might contain different forms of tau fibrils [80] that can interact with cellular membranes leading to membrane instability and increased toxicity (see [24] for review).…”

Amyloid Precursor Protein (APP) Regulates Gliogenesis and Neurogenesis of Human Neural Stem Cells by Several Signaling Pathways

“…In this context, there could be the possibility that aggregated forms of Aβ peptide (as oligomers and fibrils) could mediate some of the observed cellular effects. In previous studies, we demonstrated that the Aβ42 peptide, in its oligomeric and fibrillar state, affects the phenotypic specification of hNSCs [ 44 ]. However, in the current work, aggregated forms of Aβ peptide have not been detected, although we cannot exclude the possible effects of soluble Aβ peptides.…”

Natural antioxidants that act against Alzheimer’s disease through modulation of the NRF2 pathway: a focus on their molecular mechanisms of action

“…Peptides released by cleavage at the γ-site are then free to undergo oligomerization and subsequent fibrillation to form the characteristic plaques found in the atrophic brains of AD patients. Aβ 42 is considered more toxic because it is more prone to oligomerization and this enhances its ability to exert neurotoxic actions ( 40 ). Additionally, according to recent research, the accumulation of CTF-99 stimulates an excessive alteration in the morphology of mitochondria leading to increased production of ROS, further contributing to their abnormal function and the progression of disease ( 41 ).…”