Aug 19, 2016

Neutral Sphingomyelinase-2 Deficiency Ameliorates Alzheimer's Disease Pathology and Improves Cognition in the 5XFAD Mouse

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Michael B DinkinsErhard Bieberich

Abstract

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. We analyzed 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, se...Continue Reading

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Mentioned in this Paper

Exosomes
Familial Alzheimer Disease (FAD)
In Vivo
Abnormal Degeneration
APP protein, human
Extracellular
Ceramides
Presenilin-1
Neurons
Aggregation

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