Brain-derived extracellular vesicle proteomics reveals neuroprotection induced by the ARB candesartan in Parkinson’s disease patients

In models of Parkinson's disease (PD), angiotensin-II type-1 receptor (AT1) blockers (ARBs) mitigated the vulnerability of dopaminergic neurons, which aligns with recent transcriptomic studies of human brains showing increased susceptibility of dopaminergic neurons with high AGTR1 expression, and with epidemiological data indicating an ARB-related reduction in PD incidence. However, there is no experimental evidence in PD patients. Using a minimally invasive strategy based on the isolation of blood extracellular vesicles (EVs) from neuronal, microglial/macrophage, astrocytic, and oligodendrocytic origin, we report proteomic profiles from patients treated with the ARB candesartan. Candesartan treatment led to the differential expression of key proteins involved in PD pathogenesis: 46 in neuron-derived EVs, 48 in microglia/macrophage-derived EVs, 22 in astrocyte-derived EVs, and 92 in oligodendrocyte-derived EVs. Our findings provide the first direct molecular evidence of neuroprotective mechanisms triggered by ARBs in PD patients and support the rationale for larger clinical trials on ARB repurposing.