Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles
Abstract
:1. Introduction
2. Results
2.1. Human Ipscs-Derived Neurons Release Aggregation-Competent Tau in Exosomes
2.2. Full-Length Tau Is Present in CSF at Low Levels Both Free-Floating and Inside Exosomes
2.3. Optimization of the Method Used to Isolate Neuronal Exosomes from Plasma
2.4. Blood-Derived Neuronal Exosomes Contain Small Amounts of Aggregation-Competent Tau
2.5. Levels of Different Types of Tau in Neuronal Exosomes from Healthy Controls, AD and MCI Subjects
3. Discussion
4. Materials and Methods
4.1. Generation of Induced Neurons (Ins) from Induced Pluripotent Cells (Ipscs)
4.2. Characterization of Induced Neurons (Ins) by Live Cell Imaging and Immunocytochemistry
4.3. Isolation of Exosomes from in Conditioned Media (CM)
4.4. Western Blotting Analysis of in Cells and Exosomes
4.5. Mid-Region Tau ELISA
4.6. Full-Length Tau ELISA
4.7. Isolation of Exosomes from Human Cerebrospinal Fluid (CSF)
4.8. Plasma Samples and Isolation of Neuronal Exosomes
4.9. CD81 ELISA
4.10. Phosphorylated Threonine-181 (p181) Tau ELISA
4.11. Full-Length Tau Simoa-Based Assay
4.12. Tsg101 MSD Immunoassay
4.13. Characterization of Exosomes by Nanoparticle Tracking Analysis (NanoSight)
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
Aβ | Amyloid β-protein |
aCSF | Artificial cerebrospinal fluid |
AD | Alzheimer’s disease |
Alix | Apoptosis-linked gene 2-interacting protein X |
ANOVA | Analysis of variance |
BDNF | Brain derived neurotrophic factor |
CCDP | Crimson Clinical Discards Program |
CD81 | Cluster of differentiation 81 |
CM | Conditioned media |
CNTF | Ciliary neurotrophic factor |
CSF | Cerebrospinal fluid |
DIV | Day in vitro |
EV | Extracellular vesicle |
FL | Full-length |
GDNF | Glial derived neurotrophic factor |
HBS | Harvard Biomarker Study |
HC | Healthy control |
IgG | Immunoglobulin G |
iN | Induced neuron |
iPSC | Induced pluripotent stem cell |
L1CAM | Neural cell adhesion molecule L1 |
LLoQ | Lower limit of quantitation |
mAb | Monoclonal antibody |
MAP-2 | Microtubule-associated protein 2 |
MCI | Mild cognitive impairment |
MEM-NEAA | Minimum essential medium with non-essential amino acids |
MSD | Meso Scale Discovery |
MTBR | Microtubule binding region |
MV | Microvesicle |
MVB | Multivesicular body |
p181 | Tau phosphorylated at threonine 181 |
PrP | Prion protein |
TBST | Tris buffered saline with 0.05% Tween-20 |
Tsg101 | Tumor susceptibility gene 101 |
TOM20 | Translocase of the outer membrane-20 |
ULoQ | Upper limit of quantitation |
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HC | MCI | Mild AD | Moderate AD | |
---|---|---|---|---|
Subjects (n) | 10 | 10 | 10 | 10 |
Age (Mean ± SD) | 75.90 ± 8.67 | 76.00 ± 7.97 | 75.60 ± 12.89 | 75.00 ± 11.34 |
MMSE (Mean ± SD) | 29.67 ± 0.52 | 28.10 ± 1.20 | 22.80 ± 6.18 | 15.00 ± 5.24 |
Sex: | ||||
Female | 7 | 5 | 4 | 7 |
Male | 3 | 5 | 6 | 3 |
APOE allele: | ||||
ε4/ε4 | - | 1 | 2 | 2 |
ε4/ε3 | 3 | 2 | 4 | 4 |
ε4/ε2 | - | 1 | - | - |
ε3/ε3 | 6 | 5 | 3 | 4 |
ε3/ε2 | 1 | 1 | 1 | - |
Diagnosis | CDR | p181 tau (pg/mL) | MR tau (pg/mL) | FL tau (pg/mL) | CD81 A (ng/mL) | CD81 B (ng/mL) | CD81 Avg. (ng/mL) | Tsg101 (ng/mL) | Vesicles/mL (65–305 nm) |
---|---|---|---|---|---|---|---|---|---|
HC | 0 | 106.32 | 91.31 | 3.09 | 1.85 | 2.53 | 2.19 | 4.24 * | 7.39 × 1010 |
HC | 0 | 23.27 * | 212.09 | 9.02 | 3.09 | 3.19 | 3.14 | 6.28 * | 9.30 × 1010 |
HC | 0 | 110.09 | 564.53 | 17.14 | 12.07 | 10.21 | 11.14 | 25.34 | 6.91 × 1010 |
HC | 0 | 24.01 * | 106.49 | 17.30 | 1.89 | 2.48 | 2.18 | 17.03 | 7.75 × 1010 |
HC | 0 | 51.65 | 785.36 | 7.19 | 3.81 | 5.20 | 4.50 | 62.21 | 1.20 × 1011 |
HC | 0 | 25.21 * | 310.33 | 0.34 * | 1.38 | 1.97 | 1.67 | 8.47 * | 5.88 × 1010 |
HC | 0 | 75.76 | 415.53 | 7.46 | 3.94 | 5.59 | 4.77 | 13.52 | 4.90 × 1010 |
HC | 0 | 75.47 | 425.05 | 8.22 | 2.49 | 3.43 | 2.96 | 12.83 | 9.93 × 1010 |
HC | 0 | 159.50 | 547.89 | 13.67 | 4.81 | 6.23 | 5.52 | 26.26 | 8.64 × 1010 |
HC | 0 | 50.81 | 232.69 | 2.18 | 1.19 | 2.06 | 1.63 | 10.45 | 1.12 × 1011 |
MCI | 0.5 | 47.93 | 376.09 | 21.84 | 4.37 | 5.22 | 4.79 | 6.46 * | 1.37 × 1011 |
MCI | 0.5 | 71.93 | 109.38 | 3.74 | 2.98 | 3.83 | 3.41 | 23.66 | 5.14 × 1010 |
MCI | 0.5 | 32.98 | 375.45 | 16.79 | 2.34 | 2.73 | 2.54 | 8.07 * | 9.68 × 1010 |
MCI | 0.5 | 22.35 * | 279.21 | 11.02 | 2.42 | 3.37 | 2.90 | 7.85 * | 7.86 × 1010 |
MCI | 0.5 | 19.65 * | 653.48 | 32.91 | 2.68 | 2.62 | 2.65 | 20.22 | 9.27 × 1010 |
MCI | 0.5 | 19.29 * | 455.32 | 15.03 | 2.11 | 3.33 | 2.72 | 5.88 * | 6.73 × 1010 |
MCI | 0.5 | 47.58 | 358.76 | 2.95 | 2.30 | 3.09 | 2.70 | 10.80 | 8.13 × 1010 |
MCI | 0.5 | 249.49 | 730.90 | 17.56 | # | 113.64 | 113.64 | 617.83 # | 1.02 × 1011 |
MCI | 0.5 | 262.32 | 402.86 | 35.30 | 31.68 | 19.31 | 11.54 | 106.61 | 1.37 × 1011 |
MCI | 0.5 | 38.48 * | 375.07 | 2.74 | 2.07 | 2.47 | 9.50 | 6.00 | 7.34 × 1010 |
AD | 1 | 103.42 | 518.38 | 10.19 | 5.05 | 5.07 | 5.06 | 14.51 | 5.76 × 1010 |
AD | 1 | 461.08 | 3850.19 | 90.77 | # | 200.64 | 200.64 | 3203.27 # | 9.62 × 1010 |
AD | 1 | 69.33 | 390.15 | 3.32 | 2.23 | 3.17 | 2.70 | 8.99 * | 5.49 × 1010 |
AD | 0.5 | 101.36 | 952.47 | 10.04 | 5.50 | 6.71 | 6.11 | 113.91 | 8.26 × 1010 |
AD | 2 | 115.47 | 360.99 | 4.80 | 2.39 | 3.79 | 3.09 | 13.05 | 5.97 × 1010 |
AD | 2 | 233.30 | 152.63 | 16.61 | 7.11 | 9.09 | 8.10 | 30.39 | 8.01 × 1010 |
AD | 1 | 117.66 | 105.67 | 5.62 | 2.47 | 3.16 | 2.82 | 6.32 * | 5.30 × 1010 |
AD | 1 | 168.64 | 186.16 | 10.73 | 6.80 | 7.56 | 7.18 | 83.26 | 7.15 × 1010 |
AD | 1 | 188.85 | 337.34 | 16.71 | 4.71 | 6.75 | 5.73 | 20.00 | 1.21 × 1010 |
AD | 0.5 | 59.97 | 417.40 | 3.88 | 2.34 | 3.23 | 2.78 | 32.55 | 8.29 × 1010 |
AD | 2 | 34.95 | 490.67 | 7.25 | 2.36 | 4.13 | 3.25 | 11.66 | 6.81 × 1010 |
AD | 2 | 146.63 | 663.16 | 8.15 | 3.10 | 4.27 | 3.69 | 16.34 | 1.18 × 1011 |
AD | 2 | 118.26 | 83.97 | 8.48 | 3.86 | 5.60 | 4.73 | 8.62 * | 1.39 × 1011 |
AD | 0.5 | 43.28 | 596.59 | 44.91 | 6.58 | 5.80 | 6.19 | 42.78 | 1.09 × 1011 |
AD | 2 | 39.38 | 612.44 | 6.02 | 8.32 | 7.53 | 7.92 | 29.48 | 8.97 × 1010 |
AD | 2 | 86.36 | 555.09 | 11.91 | 2.71 | 3.80 | 3.26 | 11.00 | 1.14 × 1011 |
AD | 1 | 19.47 * | 322.82 | 16.99 | 1.51 | 2.19 | 1.85 | 7.52 * | 8.48 × 1010 |
AD | 2 | 96.47 | 5198.57 | 20.36 | 8.74 | 8.77 | 8.75 | 81.17 | 1.39 × 1011 |
AD | 2 | 226.10 | 305.60 | 12.74 | 4.69 | 6.28 | 5.49 | 14.62 | 1.89 × 1011 |
AD | 2 | 71.86 | 431.69 | 4.05 | 3.42 | 4.90 | 4.16 | 97.17 | 9.51 × 1010 |
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Share and Cite
Guix, F.X.; Corbett, G.T.; Cha, D.J.; Mustapic, M.; Liu, W.; Mengel, D.; Chen, Z.; Aikawa, E.; Young-Pearse, T.; Kapogiannis, D.; et al. Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. Int. J. Mol. Sci. 2018, 19, 663. https://doi.org/10.3390/ijms19030663
Guix FX, Corbett GT, Cha DJ, Mustapic M, Liu W, Mengel D, Chen Z, Aikawa E, Young-Pearse T, Kapogiannis D, et al. Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. International Journal of Molecular Sciences. 2018; 19(3):663. https://doi.org/10.3390/ijms19030663
Chicago/Turabian StyleGuix, Francesc X., Grant T. Corbett, Diana J. Cha, Maja Mustapic, Wen Liu, David Mengel, Zhicheng Chen, Elena Aikawa, Tracy Young-Pearse, Dimitrios Kapogiannis, and et al. 2018. "Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles" International Journal of Molecular Sciences 19, no. 3: 663. https://doi.org/10.3390/ijms19030663