Peri-arterial pathways for clearance of α-Synuclein and tau from the brain: Implications for the pathogenesis of dementias and for immunotherapy

IntroductionAccumulation of amyloid beta (A beta), alpha-synuclein (alpha Syn), and tau in dementias indicates their age-related failure of elimination from the brain. A beta is eliminated along basement membranes in walls of cerebral arterioles and leptomeningeal arteries (intramural peri-arterial drainage [IPAD]); IPAD is impaired with age. We test the hypothesis that alpha Syn and tau are also eliminated from the normal brain along IPAD pathways. MethodsSoluble alpha Syn or tau was injected into mouse hippocampus. Animals were perfused 5 minutes to 7 days post-injection. Blood vessels were identified by ROX-SE for light-sheet and immunolabeling for confocal microscopy. IPAD was quantified by measuring the proportion of arterioles with alpha Syn/tau. Results alpha Syn and tau are eliminated from the brain by IPAD but with different dynamics. DiscussionAge-related failure of IPAD may play a role in the pathogenesis of synucleinopathies and tauopathies. alpha Syn persists within IPAD at 24 hours, which may affect immunotherapy for alpha Syn.