Abstract
The accumulation of amyloid-β protein (Aβ) in brain is linked to the early pathogenesis of Alzheimer’s disease (AD). We previously reported that neuron-derived exosomes promote Aβ clearance in the brains of amyloid precursor protein transgenic mice and that exosome production is modulated by ceramide metabolism. Here, we demonstrate that plant ceramides derived from Amorphophallus konjac, as well as animal-derived ceramides, enhanced production of extracellular vesicles (EVs) in neuronal cultures. Oral administration of plant glucosylceramide (GlcCer) to APP overexpressing mice markedly reduced Aβ levels and plaque burdens and improved cognition in a Y-maze learning task. Moreover, there were substantial increases in the neuronal marker NCAM-1, L1CAM, and Aβ in EVs isolated from serum and brain tissues of the GlcCer-treated AD model mice. Our data showing that plant ceramides prevent Aβ accumulation by promoting EVs-dependent Aβ clearance in vitro and in vivo provide evidence for a protective role of plant ceramides in AD. Plant ceramides might thus be used as functional food materials to ameliorate AD pathology.
Highlights
The accumulation of amyloid-β protein (Aβ) in brain is linked to the early pathogenesis of Alzheimer’s disease (AD)
Particle counting with a nanoparticle analyser revealed that treatment with the plant ceramides increased the amounts of extracellular vesicles (EVs) and animal-type ceramides (d18:1/C18:0) in supernatants from the cultured cells (Fig. 1b), whereas treatment with GlcCer, either plant or animal, had no effect
The results from the present study reveal a novel physiological function of plant ceramides, namely, that they decrease brain Aβ levels to prevent AD-like pathologies
Summary
The accumulation of amyloid-β protein (Aβ) in brain is linked to the early pathogenesis of Alzheimer’s disease (AD). We previously reported that neuron-derived exosomes promote Aβ clearance in the brains of amyloid precursor protein transgenic mice and that exosome production is modulated by ceramide metabolism. Alzheimer’s disease (AD) is a common form of dementia with a pathology characterised by the progressive intracerebral accumulation of amyloid-β protein (Aβ). This accumulation results from impaired clearance of Aβ in the sporadic form of AD and from increased production due to genetic mutations of amyloid precursor protein (APP) or Aβ processing enzymes in the less-common familial form of AD1. We showed that oral administration of plant GlcCer to APP transgenic mice markedly reduced Aβ levels and amyloid plaques and eventually attenuated Aβ-related pathologies, such as inflammation, synaptic dysfunction and cognitive deficits. We demonstrated that plant sphingolipids increase the production of neuron-derived EVs with the ability to clear Aβ in neuronal cultures and in mice
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