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 ofdopaminergic neurons, which aligns with recent transcriptomic studies of human brains showing increased susceptibility ofdopaminergic neurons with high AGTR1 expression, and with epidemiological data indicating an ARB-related reduction in PDincidence. However, there is no experimental evidence in PD patients. Using a minimally invasive strategy based on the isolation ofblood extracellular vesicles (EVs) from neuronal, microglial/macrophage, astrocytic, and oligodendrocytic origin, we report proteomicprofiles from patients treated with the ARB candesartan. Candesartan treatment led to the differential expression of key proteinsinvolved in PD pathogenesis: 46 in neuron-derived EVs, 48 in microglia/macrophage-derived EVs, 22 in astrocyte-derived EVs, and 92in oligodendrocyte-derived EVs. Our findings provide the first direct molecular evidence of neuroprotective mechanisms triggered byARBs in PD patients and support the rationale for larger clinical trials on ARB repurposing.