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Cited by 14Extracellular vesicles in diseaseAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Relationships of APOE Genotypes With Small RNA and Protein Cargo of Brain Tissue Extracellular Vesicles From Patients With Late-Stage AD

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Huang, Yiyao, Driedonks, Tom A.P., Cheng, Lesley, Rajapaksha, Harinda, Turchinovich, Andrey, Routenberg, David A., Nagaraj, Rajini, Redding-Ochoa, Javier +8 more·2022·Neurology Genetics
DOI 10.1212/nxg.0000000000200026PMC PMC9667865
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Abstract

Background and Objectives Variants of the apolipoprotein E (APOE) gene are the greatest known risk factors for sporadic Alzheimer disease (AD). Three major APOE isoform alleles, ε2, ε3, and ε4, encode and produce proteins that differ by only 1–2 amino acids but have different binding partner interactions. Whereas APOE ε2 is protective against AD relative to ε3, ε4 is associated with an increased risk for AD development. However, the role of APOE in gene regulation in AD pathogenesis has remained largely undetermined. Extracellular vesicles (EVs) are lipid bilayer–delimited particles released by cells to dispose of unwanted materials and mediate intercellular communication, and they are implicated in AD pathophysiology. Brain-derived EVs (bdEVs) could act locally in the tissue and reflect cellular changes. To reveal whether APOE genotype affects EV components in AD brains, bdEVs were separated from patients with AD with different APOE genotypes for parallel small RNA and protein profile. Methods bdEVs from late-stage AD brains (BRAAK stages 5–6) from patients with APOE genotypes ε2/3 (n = 5), ε3/3 (n = 5), ε3/4 (n = 6), and ε4/4 (n = 6) were separated using our published protocol into a 10,000g pelleted extracellular fraction (10K) and a further purified EV fraction. Counting, sizing, and multiomic characterization by small RNA sequencing and proteomic analysis were performed for 10K, EVs, and source tissue. Results Comparing APOE genotypes, no significant differences in bdEV total particle concentration or morphology were observed. Overall small RNA and protein profiles of 10K, EVs, and source tissue also did not differ substantially between different APOE genotypes. However, several differences in individual RNAs (including miRNAs and tRNAs) and proteins in 10K and EVs were observed when comparing the highest and lowest risk groups (ε4/4 and ε2/3). Bioinformatic analysis and previous publications indicate a potential regulatory role of these molecules in AD. Discussion For patients with late-stage AD in this study, only a few moderate differences were observed for small RNA and protein profiles between APOE genotypes. Among these, several newly identified 10K and EV-associated molecules may play roles in AD progression. Possibly, larger genotype-related differences exist and are more apparent in or before earlier disease stages.

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  • APOE isoforms influence EV biogenesis and cargo through effects on lipid membrane dynamics and endosomal trafficking.

    “APOE isoforms influence EV biogenesis and cargo through effects on lipid membrane dynamics and endosomal trafficking. 28 , 29”

    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 [28]

    The Discussion section, “Does APOE Genotype Associate With bdEV Production?” (page unavailable), says APOE genotype could affect EV biogenesis and cargo loading, citing reported endosomal and lysosomal dysfunction associated with ε4. It does not establish those effects as fact or identify lipid membrane dynamics as a mechanism. The Results section, “Basic bdEV Characterization” (page unavailable), found no significant particle-count differences among genotypes in the late-stage AD samples. (LLM, conf=0.87)

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Authors
Huang, Y., Driedonks, T. A. P., Cheng, L., Rajapaksha, H., Turchinovich, A., Routenberg, D. A., Nagaraj, R., Redding-Ochoa, J., Arab, T., Powell, B. H., Pletnikova, O., Troncoso, J. C., Zheng, L., Hill, A. F., Mahairaki, V., & Witwer, K. W.
Affiliations
  • Johns Hopkins University (US)
  • From the Department of Molecular and Comparative Pathobiology (Y.H., T.A.P.D., T.A., B.H.P., K.W.W.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Biochemistry and Chemistry (L.C., H.R., A.F.H.), La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia; Molecular Epidemiology (A.T.), German Cancer Research Center DKFZ, Heidelberg, Germany; SciBerg e.Kfm (A.T.), Mannheim, Germany; Meso Scale Diagnostics (D.A.R., R.N.), LLC, Rockville, MD;...
Corresponding author
Witwer, Kenneth W.
ORCID
Venue
Neurology Genetics
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022-12
Volume
8
Issue
6
Pages
e200026-e200026
ISSN
2376-7839 (ISSN-L)
DOI
10.1212/nxg.0000000000200026
PMC
PMC9667865
OpenAlex
W4307560946
Cited by
14
References
5
Citations by year
2026: 6 · 2025: 2 · 2024: 2 · 2023: 4
FWCI
0.65
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Neurology Genetics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Victoria University Research Repository (Victoria University) (submittedVersion, cc-by-nc-nd)
  • Figshare (submittedVersion, cc-by-nc-nd)
  • La Trobe University
Funders
  • Johns Hopkins University
  • La Trobe University
  • National Institutes of Health (MH118164)
  • Medical Research Council
  • National Health and Medical Research Council (1132604)
  • National Institute on Aging (U19AG033655, R56AG057430, P30AG066507)
  • National Institute of Mental Health (UH3MH118167, UH2MH118167, R21MH118164, R33MH118164)
  • National Institute on Drug Abuse (R01DA047807)
  • NIH Office of the Director (UG3CA241694)
  • National Cancer Institute (UH3CA241694, UG3CA241694)
  • National Institute of Allergy and Infectious Diseases (R01AI144997)
  • Office of Strategic Coordination (UG3CA241694)
  • Common Fund (UG3CA241694)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E, APOE ε4, Alzheimer's disease, brain-derived extracellular vesicles, small RNA, microRNA, tRNA, extracellular vesicle proteome, APOE genotype, intercellular communication, biomarkers, APOE ε2, APOE ε3, Braak stages

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