Proteomic analysis of blood neuronal and glial extracellular vesicles reveals neuroprotective effects of the angiotensin type-1 blocker candesartan in Parkinson's disease patients

BackgroundThe renin-angiotensin system (RAS) is a major regulator of cell homeostasis, oxidative stress, and inflammatory responses in different tissues, including the brain. In Parkinsons disease (PD) models, activation of angiotensin type-1 receptors (AT1) increased the vulnerability of dopaminergic neurons, which was inhibited by AT1 blockers (ARBs). This is consistent with recent studies in human brains showing the highest vulnerability of the dopaminergic neurons with the highest rate of the AT1 gene (AGTR1) expression, and retrospective cohort studies showing a reduction of PD risk in patients receiving ARB treatment. Neuroprotective effects of ARBs have also been suggested for Alzheimers disease. MethodsWe recently performed a randomized phase-II 28-week clinical trial of the ARB candesartan in PD. However, the molecular changes induced by ARBs with BBB-penetrating properties such as candesartan in the brain of PD patients remain unexplored. In PD patients, we used a minimally invasive approach to characterize cell- type-specific molecular changes induced by candesartan in the brain. We obtained extracellular vesicles (EVs) from neurons and different types of glial cells within the same blood sample, and the protein content was compared before and after candesartan treatment. ResultsCandesartan induced the upregulation or downregulation of many proteins relevant to PD progression. These changes were detected in EVs derived from neurons (46 dysregulated proteins), microglia/macrophages (48 dysregulated proteins), astrocytes (22 dysregulated proteins), and oligodendrocytes (92 dysregulated proteins). Altogether, the proteomic changes indicate a coordinated neuroprotective response, involving improved redox and mitochondrial function, enhanced proteostasis and gene regulation, and attenuation of synaptic, metabolic, and inflammatory stress pathways. ConclusionOur proteomic analysis indicates the neuroprotective effects of ARBs such as candesartan on neurons and glial cells in PD patients, highlighting its therapeutic potential and suggesting the need of larger clinical trials for repurposing of these drugs. The results also reveal the potential of the present minimally invasive approach to detect brain cell-type-specific molecular changes and points to a shift in neurodegenerative disease research and monitoring.