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

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.</p

A Randomized First-in-Human Study With UB-312, a UBITh (R) alpha-Synuclein Peptide Vaccine

Background: alpha-Synuclein (alpha Syn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic alpha Syn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar alpha Syn, making UB-312 a potential immunotherapeutic for synucleopathies.Objective: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study.Methods: Fifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, double-blind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 mu g). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-aSyn antibody concentrations.Results: Twenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose- and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 mu g UB-312 dose regimen. The average CSF/serum ratio was 0.2%.Conclusions: UB-312 was generally safe, well tolerated, and induced anti-aSyn antibodies in serum and CSF of healthy participants. The 100 and 300 mu g doses are selected for further evaluation in participants with PD. (C) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ