Recent evidence implicates exosomes in the aggregation of Aβ and spreading of tau in Alzheimer’s disease. In neural cells, exosome formation can be blocked by inhibition or silencing of neutral sphingomyelinase-2 (nSMase2). We generated genetically nSMase2- deficient 5XFAD mice (fro;5XFAD) to assess AD-related pathology in a mouse model with consistently reduced ceramide generation. We conducted in vitro assays to assess Aβ42 aggregation and glial clearance with and without exosomes isolated by ultracentrifugation and determined exosome-induced amyloid aggregation by particle counting.Weanalyzed brain exosome content, amyloid plaque formation, neuronal degeneration, sphingolipid, Aβ42 and phospho-tau levels, and memory-related behaviors in 5XFAD versus fro;5XFAD mice using contextual and cued fear conditioning. Astrocyte-derived exosomes accelerated aggregation of Aβ42 and blocked glial clearance of Aβ42 in vitro. Aβ42 aggregates were colocalized with extracellular ceramide in vitro using a bifunctional ceramide analog preloaded into exosomes and in vivo using anticeramide IgG, implicating ceramide-enriched exosomes in plaque formation. Compared with 5XFAD mice, the fro;5XFAD mice had reduced brain exosomes, ceramide levels, serum anticeramide IgG, glial activation, total Aβ42 and plaque burden, tau phosphorylation, and improved cognition in a fear-conditioned learning task. Ceramide-enriched exosomes appear to exacerbate AD-related brain pathology by promoting the aggregation of Aβ. Reduction of exosome secretion by nSMase2 loss of function improves pathology and cognition in the 5XFAD mouse model.
|Number of pages||15|
|Journal||Journal of Neuroscience|
|State||Published - Aug 17 2016|
Bibliographical noteFunding Information:
This work was supported by the National Institute on Aging–National Institutes of Health (Grant R01-AG034389 to E.B. and Grant F32-044954 to M.B.D.). The funding agency had no role in study design, data collection, decision to publish, or manuscript preparation. We thank the staff of the imaging core (Drs. Ana and Paul McNeil and Tim Kurtz) and the small animal behavior core facilities at Augusta University and the lipidomics core facility at the Medical University of South Carolina (Dr. Jacek Bielawski). We also acknowledge institutional support for the ZetaView instrument from the Office of the Senior Vice President for Research, Cancer Center, Department of Neuroscience and Regenerative Medicine (Dr. Lin Mei, chair), and the Vascular Biology Center at Augusta University.
© 2016 the authors.
- Fear conditioning
ASJC Scopus subject areas
- Neuroscience (all)