Modelling glucose neurotoxicity in iPSC-derived dopaminergic neurons and glia cells reveals the neuroprotective potential of p75NTR targeting

ABSTRACT: Hyperglycemia, a hallmark of Diabetes Mellitus, consists a metabolic condition that can lead to severe complications in the nervous system, significantly increasing the risk for neurodegenerative disorders. Evidence from epidemiological studies and animal models suggests that diabetes influences the dopaminergic system and the development of Parkinson’s Disease, however the mechanistic interlink is still unclear. To this end, our aim is to investigate the direct and the glial-cell mediated effects of high glucose on neurodegeneration using a human model of iPSC-derived neural cells. Considering previous implication of the pan-neurotrophin p75NTR receptor in the neurological complications of diabetes in the PNS and retina we investigated for the first time its role in glucose neurotoxicity in the brain. Dopaminergic neurons, astrocytes and microglia were differentiated from human iPSC and were exposed to high glucose (100mM) for 48h to simulate hyperglycemia. Cytotoxicity, immunofluorescence and RNA-seq analyses were used to investigate the effect of hyperglycemia on dopaminergic neurons and the role of p75NTR receptor. ELISA was used to quantify the levels of pro-NGF. Astrocyte and microglia conditioned media were used for neuronal treatments to investigate changes in neuronal-glial cell communication in hyperglycemia. Hyperglycemia led to DNA damage, activation of the JNK kinase and significant cell death of dopaminergic neurons. Glucose overload increased neuronal susceptibility to the cytotoxic effect of 6-OHDA and Amyloid-β. We identified an up-regulation of both pro-NGF, a pro-apoptotic ligand of p75NTR, and p75NTR levels in high glucose-treated neurons, while inhibition of p75NTR activity rescued neuronal cell death, indicating p75NTR as a key mediator of glucose neurotoxicity. In accordance, BNN27, a synthetic activator of p75NTR exerted neuroprotective effects against glucotoxicity in dopaminergic neurons. Finally, we assessed the contribution of glial cells to neurodegeneration in hyperglycemic conditions. Exposure of iPSC-derived astrocytes and microglia to high glucose induced the secretion of neurotoxic factors with a secondary pro-apoptotic effect on dopaminergic neurons. Our study provides insights into the mechanism of glucose neurotoxicity in human dopaminergic neurons, suggests the therapeutic potential of targeting the pro-apoptotic pro-NGF/p75NTR axis and highlights the involvement of glial cells in dopaminergic neurodegeneration in diabetic encephalopathy. Our results underline the importance of glycemic control in patients with PD predisposition to delay disease onset and progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291145 | GEO | 2026/03/31

REPOSITORIES: GEO