High complement levels in astrocyte-derived exosomes of Alzheimer disease

Edward J. Goetzl, Janice B. Schwartz, Erin L. Abner, Gregory A. Jicha, Dimitrios Kapogiannis

Research output: Contribution to journalArticlepeer-review

228 Scopus citations

Abstract

Objective: Astrocytes fulfill neuronal trophic roles normally, but are transformed in Alzheimer disease (AD) into A1-type reactive astrocytes that may destroy neurons through unknown mechanisms. Methods: To investigate astrocyte inflammatory mechanisms, astrocyte-derived exosomes (ADEs) were isolated immunochemically from plasma samples of AD patients and matched controls for enzyme-linked immunosorbent assay quantification of complement proteins. Results: ADE levels of C1q, C4b, C3d, factor B, factor D, Bb, C3b, and C5b-C9 terminal complement complex, but not mannose-binding lectin, normalized by the CD81 exosome marker were significantly higher for AD patients (n = 28) than age- and gender-matched controls (all p < 0.0001). ADE normalized levels of interleukin (IL)-6, tumor necrosis factor-α, and IL-1β were significantly higher for AD patients than controls, but there was greater overlap between the two groups than for complement proteins. Mean ADE levels of complement proteins for AD patients in a longitudinal study were significantly higher (n = 16, p < 0.0001) at the AD2 stage of moderate dementia than at the AD1 preclinical stage 5 to 12 years earlier, which were the same as for controls. ADE levels of complement regulatory proteins CD59, CD46, decay-accelerating factor (DAF), and complement receptor type 1, but not factor I, were significantly lower for AD patients than controls (p < 0.0001 for CD59 and DAF), were diminished by the AD1 stage, and were further decreased at the AD2 stage. Interpretation: ADE complement effector proteins in AD are produced by dysregulated systems, attain higher levels than in controls, and may potentially damage neurons in the late inflammatory phase of AD. Ann Neurol 2018;83:544–552.

Original languageEnglish
Pages (from-to)544-552
Number of pages9
JournalAnnals of Neurology
Volume83
Issue number3
DOIs
StatePublished - Mar 2018

Bibliographical note

Publisher Copyright:
© 2018 American Neurological Association

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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