Impact of Suramin on Key Pathological Features of Sporadic Alzheimer's Disease-Derived Forebrain Neurons.

Autor:	Culibrk RA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA., Ebbert KA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA., Yeisley DJ; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA., Chen R; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA., Qureshi FA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA., Hahn J; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA., Hahn MS; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA.; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.
Jazyk:	angličtina
Zdroj:	Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2024; Vol. 98 (1), pp. 301-318.
DOI:	10.3233/JAD-230600
Abstrakt:	Background: Alzheimer's disease (AD) is characterized by disrupted proteostasis and macroautophagy (hereafter "autophagy"). The pharmacological agent suramin has known autophagy modulation properties with potential efficacy in mitigating AD neuronal pathology. Objective: In the present work, we investigate the impact of forebrain neuron exposure to suramin on the Akt/mTOR signaling pathway, a major regulator of autophagy, in comparison with rapamycin and chloroquine. We further investigate the effect of suramin on several AD-related biomarkers in sporadic AD (sAD)-derived forebrain neurons. Methods: Neurons differentiated from ReNcell neural progenitors were used to assess the impact of suramin on the Akt/mTOR signaling pathway relative to the autophagy inducer rapamycin and autophagy inhibitor chloroquine. Mature forebrain neurons were differentiated from induced pluripotent stem cells (iPSCs) sourced from a late-onset sAD patient and treated with 100μM suramin for 72 h, followed by assessments for amyloid-β, phosphorylated tau, oxidative/nitrosative stress, and synaptic puncta density. Results: Suramin treatment of sAD-derived neurons partially ameliorated the increased p-Tau(S199)/Tau ratio, and fully remediated the increased glutathione to oxidized nitric oxide ratio, observed in untreated sAD-derived neurons relative to healthy controls. These positive results may be due in part to the distinct increases in Akt/mTOR pathway mediator p-p70S6K noted with suramin treatment of both ReNcell-derived and iPSC-derived neurons. Longer term neuronal markers, such as synaptic puncta density, were unaffected by suramin treatment. Conclusions: These findings provide initial evidence supporting the potential of suramin to reduce the degree of dysregulation in sAD-derived forebrain neurons in part via the modulation of autophagy.
Databáze:	MEDLINE
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