Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons

• High glucose induces DNA damage, JNK activation, and cell death in iPSC-derived dopaminergic neurons, mimicking hyperglycemic neurotoxicity. • The pro-NGF/p75NTR axis is upregulated under hyperglycemic conditions, and pharmacological inhibition of p75NTR rescues neuronal death, identifying p75NTR as a key mediator. • Glucose overload sensitizes neurons to 6-OHDA toxicity, an effect reversed by p75NTR blockade, suggesting a link between diabetes and Parkinson's disease vulnerability. • The synthetic NGF mimetic BNN27 protects neurons via p75NTR and TrkA receptors, offering a potential therapeutic strategy for diabetic neurodegeneration.