Min Shi1, Andrej Kovac2, Ane Korff1, Travis J Cook1, Carmen Ginghina1, Kristin M Bullock3, Li Yang1, Tessandra Stewart1, Danfeng Zheng4, Patrick Aro1, Anzari Atik1, Kathleen F Kerr5, Cyrus P Zabetian6, Elaine R Peskind7, Shu-Ching Hu6, Joseph F Quinn8, Douglas R Galasko9, Thomas J Montine1, William A Banks3, Jing Zhang10. 1. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA. 2. Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic. 3. Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA. 4. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA; Department of Pathology, Peking University Health Science Center and Peking University Third Hospital, Beijing, China. 5. Department of Biostatistics, University of Washington, Seattle, WA, USA. 6. Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. 7. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA; Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. 8. Department of Neurology, Oregon Health and Science University, Portland, OR, USA. 9. Department of Neurosciences and Shiley-Marcos Alzheimer's Disease Research Center, University of California at San Diego, La Jolla, CA, USA. 10. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA; Department of Pathology, Peking University Health Science Center and Peking University Third Hospital, Beijing, China. Electronic address: zhangj@uw.edu.
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.
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 ADpatients, L1CAM exosomal tau was significantly higher in PDpatients 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
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