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Cited by 283Alzheimer's disease research and treatmentsExtracellular vesicles in diseaseDementia and Cognitive Impairment Research

Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons

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Ruan, Zhi, Pathak, Dhruba, Venkatesan Kalavai, Srinidhi, Yoshii-Kitahara, Asuka, Muraoka, Satoshi, Bhatt, Nemil, Takamatsu-Yukawa, Kayo, Hu, Jianqiao +9 more·2021·Brain
DOI 10.1093/brain/awaa376PMC PMC7880668

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Abstract

Extracellular vesicles are highly transmissible and play critical roles in the propagation of tau pathology, although the underlying mechanism remains elusive. Here, for the first time, we comprehensively characterized the physicochemical structure and pathogenic function of human brain-derived extracellular vesicles isolated from Alzheimer’s disease, prodromal Alzheimer’s disease, and non-demented control cases. Alzheimer’s disease extracellular vesicles were significantly enriched in epitope-specific tau oligomers in comparison to prodromal Alzheimer’s disease or control extracellular vesicles as determined by dot blot and atomic force microscopy. Alzheimer’s disease extracellular vesicles were more efficiently internalized by murine cortical neurons, as well as more efficient in transferring and misfolding tau, than prodromal Alzheimer’s disease and control extracellular vesicles in vitro. Strikingly, the inoculation of Alzheimer’s disease or prodromal Alzheimer’s disease extracellular vesicles containing only 300 pg of tau into the outer molecular layer of the dentate gyrus of 18-month-old C57BL/6 mice resulted in the accumulation of abnormally phosphorylated tau throughout the hippocampus by 4.5 months, 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. Furthermore, Alzheimer’s disease extracellular vesicles induced misfolding of endogenous tau in both oligomeric and sarkosyl-insoluble forms in the hippocampal region. Unexpectedly, phosphorylated tau was primarily accumulated in glutamic acid decarboxylase 67 (GAD67) GABAergic interneurons and, to a lesser extent, glutamate receptor 2/3-positive excitatory mossy cells, showing preferential extracellular vesicle-mediated GABAergic interneuronal tau propagation. Whole-cell patch clamp recordings of CA1 pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+ neurons and GAD67+ neuronal puncta surrounding pyramidal neurons in the CA1 region, confirming reduced GABAergic transmission in this region. Our study posits a novel mechanism for the spread of tau in hippocampal GABAergic interneurons via brain-derived extracellular vesicles and their subsequent neuronal dysfunction.

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  • In AD, EVs contribute to tau propagation, neuroinflammatory signaling, astrocyte activation, and vascular dysfunction.

    “In AD, EVs contribute to tau propagation, neuroinflammatory signaling, astrocyte activation, and vascular dysfunction. 21 , 22 , 23 , 24 , 25”

    From Plasma extracellular vesicles from <i>APOE3</i> Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease (2026) · cites this paper as [21]

    The Discussion reports that Alzheimer’s disease EVs initiate tau propagation in mice. Its discussion of inflammation describes inflammatory conditions affecting EV composition and uptake, not EVs causing neuroinflammatory signaling. The cited passages do not establish that EVs activate astrocytes or cause vascular dysfunction; page numbers are unavailable in our copy. (LLM, conf=0.88)

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Authors
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, H. E., Kayed, R., Ikezu, S., Luebke, J. I., & Ikezu, T.
Affiliations
  • Boston University (US)
  • Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
  • The University of Texas Medical Branch at Galveston (US)
  • Harvard University (US)
  • University of Nebraska Medical Center (US)
Corresponding author
Ikezu, Seiko
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2020-11-27
Volume
144
Issue
1
Pages
288-309
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awaa376
PMC
PMC7880668
OpenAlex
W3107708884
Cited by
283
References
16
Citations by year
2026: 45 · 2025: 55 · 2024: 57 · 2023: 55 · 2022: 48 · 2021: 21 · 2020: 2
FWCI
18.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • NIH (R01 AG066429, RF1 AG054199, R01 AG054672, R56 AG057469, R21 NS104609, R01AG054025, R01NS094557, P30 AG013846)
  • Alzheimer’s Association (AARF-9550302678)
  • Cure Alzheimer’s Fund
  • BrightFocus Foundation (A2016551S)
  • CurePSP
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, extracellular vesicles, tau pathology, tau oligomers, tau misfolding, prodromal Alzheimer's disease, GABAergic interneurons, GAD67, mossy cells, hippocampus, dentate gyrus, GABAergic neurotransmission, tau phosphorylation, disease propagation, mouse model
MeSH terms
Extracellular Vesicles, Alzheimer Disease, Animals, Brain, Female, Hippocampus, Humans, Interneurons, Male, Mice, Inbred C57BL, tau Proteins, Pyramidal Cells, Mice, GABAergic Neurons

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