Angiotensin type 1 receptor activation promotes neuronal and glial alpha-synuclein aggregation and transmission

The brain renin-angiotensin system (RAS) has been related to dopaminergic degeneration, and high expression of the angiotensin II (AngII) type 1 receptor (AT1) gene is a marker of the most vulnerable neurons in humans. However, it is unknown whether AngII/AT1 overactivation affects α-synuclein aggregation and transmission. In vitro, AngII/AT1 activation increased α-synuclein aggregation in dopaminergic neurons and microglial cells, which was related to AngII-induced NADPH-oxidase activation and intracellular calcium raising. In mice, AngII/AT1 activation was involved in MPTP-induced increase in α-synuclein expression and aggregation, as they significantly decreased in mice treated with the AT1 blocker telmisartan and AT1 knockout mice. Cell co-cultures (transwells) revealed strong transmission of α-synuclein from dopaminergic neurons to astrocytes and microglia. AngII induced a higher α-synuclein uptake by microglial cells and an increase in the transfer of α-synuclein among astroglial cells. However, AngII did not increase the release of α-synuclein by neurons. The results further support brain RAS dysregulation as a major mechanism for the progression of Parkinson’s disease, and AT1 inhibition and RAS modulation as therapeutic targets.