Ruan Z, Pathak D, Venkatesan Kalavai S, Yoshii-Kitahara A, Muraoka S, Bhatt N, Takamatsu-Yukawa K, Hu J, Wang Y, Hersh S, Ericsson M, Gorantla S, Gendelman HE, Kayed R, Ikezu S, Luebke JI, Ikezu T. Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain. 2021 Feb 12;144(1):288-309. PubMed. Correction.

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  1. This study provides novel and valuable information on the role of extracellular vesicles (EVs) in the spread of pathogenic tau oligomers and propagation of tau pathology in AD.

    The study’s notable strengths include a powerful demonstration that EVs contain cargo of hyperphosphorylated tau oligomers, important experimental controls (e.g., demonstration of preserved tau cargo after degradation of extravesicular proteins), and immunogold electron microscopy evidence. The data, among other implications, reinforce the view that neuronal EVs may serve as tau biomarkers for clinical and preclinical Alzheimer’s disease, something that my lab and others have been advocating for some time.

    Moreover, particularly important is the evidence that EVs of Alzheimer’s patients are more capable of seeding tau pathology in old mice than are purified tau oligomers or fibrils. This suggests that blocking the release of EVs containing tau seeds or blocking their uptake by unaffected neurons may have therapeutic potential in AD.

    Finally, the finding that pathogenic EVs preferentially target GABAergic neurons, at least in mice, opens avenues for future research, as it is not immediately clear which characteristics of GABAergic neurons are responsible for this preferential targeting.

    Overall, this study strengthens the view that EVs are important for AD pathogenesis and provides strong motivation for continued research on the topic.

    View all comments by Dimitrios Kapogiannis

  2. The Ikezu lab has published a series of pioneering papers on the role of exosomes/extracellular vesicles (EVs) in neurodegeneration, notably the role of exosomes in the spreading of tau pathology via microglia (Asai et al., 2015). The distinction between exosomes and EVs tends to be fuzzy, depending on size (exosomes are smaller, <100 nm) and other criteria. In this new study, Ruan et al. used the more general term EVs, but similar preparation as before.

    They compared the physicochemical structure and pathogenic function of EVs isolated from brains of Alzheimer’s disease (AD), prodromal Alzheimer’s disease (pAD), and non-demented control cases. They found that AD EVs contained a much higher amount of epitope-specific tau oligomers (positive for tau-monomer-specific antibody TOMA1 and TOMA2, but not for TOMA3) than pAD and control EVs.

    In vitro, compared with pAD and control EVs, AD EVs showed higher uptake and transfer efficiency of tau to cultured murine neurons and higher seeding activity measured by a FRET-based seeding assay. In vivo, pAD and AD EVs were more efficient in seeding and propagating tau pathology than control EVs and isolated tau oligomers and fibrils. The evidence is that the inoculation of AD or pAD EVs (containing only 300 pg of tau) into the outer molecular layer of the dentate gyrus of wild-type mice induced aggregation of endogenous tau demonstrated by the formation of sarkosyl insoluble tau, whereas inoculation of an equal amount of tau from control extracellular vesicles, isolated tau oligomers, or fibrils from the same Alzheimer’s disease donor showed little tau pathology, as judged by AT8 positive staining.

    Intriguingly, pAD or AD EVs preferentially mediated tau propagation in GABAergic interneurons. They did so to a much lesser extent in excitatory mossy cells positive for glutamate receptors 2/3, leading to reduced GABAergic transmission in this region. This study raises several interesting questions.

    1. In contrast to other studies (Dujardin et al., 2014; Kanmert et al., 2015; Wang et al., 2017), the authors isolated EVs from brain tissue instead of CSF or ISF; therefore contamination with intracellular vesicles released during the dissociation of brain tissues cannot be excluded. They performed a proteinase K assay to distinguish between proteins inside EVs, which are not digested by proteinase K because they are protected by the EV membrane, and proteins peripherally associated with EVs, which can be cleared by proteinase K. They found that PHF1+ tau, i.e., tau reacting with the phosphorylation-sensitive antibody PHF-1, in the sarkosyl-insoluble fraction was not reduced by proteinase K, whereas PHF1+ tau in the soluble fraction was dramatically decreased. They concluded that insoluble PHF1+ tau aggregates were mostly inside EVs, whereas oligomers could be peripherally associated with EVs. Interestingly, only oligomers, but not fibrils, were peripherally associated with EVs.
    2. We note, however, that an alternative explanation could be that tau oligomers but not fibrils were isolated with EVs in the same fraction in sucrose gradient centrifugation, because they display similar density as EVs.
    3. Compared to control EVs, pAD EVs showed no significant difference in uptake, transfer of tau, and seeding activity (measured by FRET assay), in cultured neurons. So when inoculated in mouse brain, why did only the pAD EVs but not the control EVs induce a pathological response of endogenous tau?
    4. One remarkable result of this study was that the inoculation of pAD or AD EVs in the hippocampus of mice preferentially induced the hallmarks of tau pathology in GABAergic interneurons. This contrasts with the more general observation that tau pathology particularly afflicts highly interconnected, glutamatergic projection neurons, leaving GABAergic interneurons largely intact (see review Arnsten et al., 2020). More research is needed to address this issue. In addition, it would be of interest to identify what components in the AD EVs determine their selection to GABAergic interneurons.

    The authors noted that inoculation of AD or pAD EVs in mouse brain induced AT8-positive tau in female mice but not in male mice, but they did not show the results and did not comment on this phenomenon. Given the different occurrence of AD between men and women, it would be interesting to test whether such EVs displayed different seeding activity between male and female mice.

    References:

    Arnsten AF, Datta D, Tredici KD, Braak H. Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer's disease. Alzheimers Dement. 2021 Jan;17(1):115-124. Epub 2020 Oct 19 PubMed.

    Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015 Nov;18(11):1584-93. Epub 2015 Oct 5 PubMed.

    Dujardin S, Bégard S, Caillierez R, Lachaud C, Delattre L, Carrier S, Loyens A, Galas MC, Bousset L, Melki R, Aurégan G, Hantraye P, Brouillet E, Buée L, Colin M. Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS One. 2014;9(6):e100760. Epub 2014 Jun 27 PubMed.

    Kanmert D, Cantlon A, Muratore CR, Jin M, O'Malley TT, Lee G, Young-Pearse TL, Selkoe DJ, Walsh DM. C-Terminally Truncated Forms of Tau, But Not Full-Length Tau or Its C-Terminal Fragments, Are Released from Neurons Independently of Cell Death. J Neurosci. 2015 Jul 29;35(30):10851-65. PubMed.

    Wang Y, Balaji V, Kaniyappan S, Krüger L, Irsen S, Tepper K, Chandupatla R, Maetzler W, Schneider A, Mandelkow E, Mandelkow EM. The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener. 2017 Jan 13;12(1):5. PubMed.

    Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4506-10. PubMed.

    Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4506-10. PubMed.

    View all comments by Eckhard Mandelkow

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