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

Abstract

Abstract 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

• Immunotherapy
• IPAD
• perivascular drainage
• tau
• α‐synuclein