Exosome-associated Tau Is Secreted in Tauopathy Models and Is Selectively Phosphorylated in Cerebrospinal Fluid in Early Alzheimer Disease*
By Sudad Saman, WonHee Kim, Mario Raya, Yvonne Visnick, Suhad Miro, S. Saman, B. Jackson, Ann C. McKee, Victor E. Alvarez, Norman C. Y. Lee and 1 more. Journal of Biological Chemistry, 2011
922 citations recorded by the source corpus.
Background: Tau is secreted unconventionally, possibly explaining increased CSF phosphotau levels in early AD. Results: M1C cells secrete selectively phosphorylated, exosomal tau. These characteristics in early AD CSF tau suggest that CSF tau is secreted, not shed from dead neurons. Conclusion: Tau secretion occurs early and may explain lesion spreading in AD. Significance: Secretion biomarkers may become revolutionary prospective AD diagnostics. Recent demonstrations that the secretion, uptake, and interneuronal transfer of tau can be modulated by disease-associated tau modifications suggest that secretion may be an important element in tau-induced neurodegeneration. Here, we show that much of the tau secreted by M1C cells occurs via exosomal release, a widely characterized mechanism that mediates unconventional secretion of other aggregation-prone proteins (α-synuclein, prion protein, and β-amyloid) in neurodegenerative disease. Exosome-associated tau is also present in human CSF samples and is phosphorylated at Thr-181 (AT270), an established phosphotau biomarker for Alzheimer disease (AD), in both M1C cells and in CSF samples from patients with mild (Braak stage 3) AD. A preliminary analysis of proteins co-purified with tau in secreted exosomes identified several that are known to be involved in disease-associated tau misprocessing. Our results suggest that exosome-mediated secretion of phosphorylated tau may play a significant role in the abnormal processing of tau and in the genesis of elevated CSF tau in early AD.
Subfields: Aerospace Engineering, Materials Chemistry, Safety, Risk, Reliability and Quality
View Paper: https://www.semanticscholar.org/paper/6cd46108274200b087a0bc61fe1b1c94db531ca5
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In Materials Chemistry
Citations in the corpus
- Review of the Isolation, Characterization, Biological Function, and Multifarious Therapeutic Approaches of Exosomes (2019, background): “Exosomes containing amyloid peptides tau-ph sphorylated at Thr-181 are potential biomarkers for Alzheimer’s diseas [202,203].”
- Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Although evidence indicates that exosomes, neuronal activity, and unconventional secretory pathways are involved in tau spreading, mechanisms underlying tau release are poorly understood [248].”
- Classification, Functions, and Clinical Relevance of Extracellular Vesicles (2012, background): “For example, exosomes in cerebrospinal fluid of patients with Alzheimer’s disease contain phosphorylated at Thr181, which is an established biomarker of this disease (Saman et al., 2012).”
- Trans-Synaptic Spread of Tau Pathology In Vivo (2012, neutral): “AD patients [14].”
- Physiological release of endogenous tau is stimulated by neuronal activity (2013, positive): “Studies in cells overexpressing exogenous tau have suggested that tau release might be mediated by exosomes and/or membrane vesicles [7–9].”
- Standardization of sample collection, isolation and analysis methods in extracellular vesicle research (2013, positive): “There is also interest in identifying the key players (cid:2) proteins and RNAs (cid:2) in unconventional EV release mechanisms prominent in neurodegenerative disease pathogenesis (209).”
- Characterization of human plasma-derived exosomal RNAs by deep sequencing (2013, background): “To date, the microvesicles have been detected in blood (plasma and serum), bronchoalveolar lavage, urine, bile, ascites, breast milk, and cerebrospinal fluid [8,11-26].”