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

Alzheimers Dement (Amst). 2020 Jul 28;12(1):e12070. doi: 10.1002/dad2.12070. eCollection 2020.


Introduction: Accumulation of amyloid beta (Aβ), α-synuclein (αSyn), and tau in dementias indicates their age-related failure of elimination from the brain. Aβ 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 αSyn and tau are also eliminated from the normal brain along IPAD pathways.

Methods: Soluble αSyn 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 αSyn/tau.

Results: αSyn and tau are eliminated from the brain by IPAD but with different dynamics.

Discussion: Age-related failure of IPAD may play a role in the pathogenesis of synucleinopathies and tauopathies. αSyn persists within IPAD at 24 hours, which may affect immunotherapy for αSyn.

Keywords: IPAD; Immunotherapy; perivascular drainage; tau; α‐synuclein.