CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease

Abstract

Introduction: Alzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood.

Methods: Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects.

Results: The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau.

Conclusions: Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

Keywords: Alzheimer's disease; Biomarkers; Blood plasma; Central nervous system protein efflux; Central nervous system-derived exosomes; Parkinson's disease; Tau.

Fig. 1. Transportation of tau from the brain to blood

(a–b) Mice were intracerebroventricularly injected with ¹²⁵I-labeled tau 2N4R (I-Tau). Brain (a) and blood plasma (b) were then collected at indicated time points after injection. Levels of radioactivity in the samples were determined using a gamma counter. See also Supplementary Fig. 1a for the early phase efflux kinetics of I-Tau. (c) Blood was collected at 60 min after injection, followed by anti-L1CAM immunocapture of exosomes from platelet-free plasma. Normal mouse IgG-captured (mIgG) or “Empty” (no bead “capture”) samples were used as controls. Levels of radioactivity were measured in the whole brain, the whole plasma, the plasma L1CAM-containing exosome fraction (Exo), and the exosome-less fraction (supernatant after immunoaffinity capture; Super). Data shown are mean ± S.D. from 4–6 mice at each time point. CPM, counts per minute.

Fig. 2. Evaluation of plasma exosomal tau concentrations in clinical samples

Tau concentrations were measured using Quanterix Simoa and comparisons were performed for tau in L1CAM-containing exosomes isolated from plasma, total tau in whole plasma in patients with Alzheimer disease (AD; n=106), patients with Parkinson disease (PD; n=91) and healthy controls (CO; n=106). (a) Mean plasma exosomal tau was higher in PD than in healthy control subjects (p=0.038, ANOVA) and AD (p=0.064). (b) Mean whole plasma tau concentration, in contrast, was significantly higher in AD compared to PD (p<0.001) or healthy controls (p<0.001). (c) A significant correlation between the plasma exosomal tau and the disease duration was observed in PD patients (r=0.286, p=0.015, Pearson correlation). (d) Additionally, a significant correlation between the whole plasma tau and the disease severity indexed by the MMSE was observed in AD patients (r=−0.233, p=0.025). Tau concentrations were Log10 transformed to generate a more normally distributed dataset. *, p<0.05; ***, p<0.001.