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Pait MC, Kaye SD, Su Y, Kumar A, Singh S, Gironda SC, Vincent S, Anwar M, Carroll CM, Snipes JA, Lee J, Furdui CM, Deep G, Macauley SL. Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV-ISF) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology. bioRxiv. 2023 Mar 12; PubMed.
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Mayo Clinic Florida
This is a technically challenging study to determine the actual composition of extracellular vesicles (EVs) in the interstitial fluid (ISF). The authors carefully conducted the experiment, and the proteomic results are exciting.
The innovation is the use of in vivo microdialysis to collect and monitor EVs from the hippocampal ISF of live mice. They applied this method to isolate ISF EVs from APP/PS1 mice of different ages and sexes and characterized the EV proteomics. The proteins in their ISF EVs showed some overlap with our previous EV dataset from CAST_APPPS1 mouse brain (Muraoka et al., 2021). By examining the cell-type-specific signatures of ISF EVs, they found that microglial EV proteins were most significantly correlated with Aβ pathology. They also observed a sexual dimorphism in the ISF EV proteome, suggesting that female APP/PS1 mice may respond differently to Aβ deposition from APP/PS1 males. The data suggest that microglial-derived EVs could serve as an attractive early biomarker of Aβ-related changes in the brain.
Our more recent proteomic profiling of brain-derived EVs isolated from AD, MCI controls show enrichment of activated astrocytes in AD cases compared to MCI or control cases (You et al., 2022).
One limitation of this study is the potential low EV yield from the microdialysis, and the possibility that the cell-type enrichment of EVs may be artificially affected by the location of insertion of the probe into the brain. Another consideration is the potential complication by the surgery to cause inflammatory responses in the mouse brain, which could alter the EV cargo composition, especially those of microglial EVs. The study is nonetheless very interesting and will provide resource for our understanding of CNS EV biology in healthy and disease conditions.
Yang You, Ph.D., of the Mayo Clinic is a co-author of this comment.
References:
Muraoka S, Jedrychowski MP, Iwahara N, Abdullah M, Onos KD, Keezer KJ, Hu J, Ikezu S, Howell GR, Gygi SP, Ikezu T. Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer's Disease Mouse Models. J Proteome Res. 2021 Mar 5;20(3):1733-1743. Epub 2021 Feb 3 PubMed.
You Y, Muraoka S, Jedrychowski MP, Hu J, McQuade AK, Young-Pearse T, Aslebagh R, Shaffer SA, Gygi SP, Blurton-Jones M, Poon WW, Ikezu T. Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer's disease brain. J Extracell Vesicles. 2022 Jan;11(1):e12183. PubMed.
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