Plant sphingolipids promote extracellular vesicle release and alleviate amyloid-β pathologies in a mouse model of Alzheimer’s disease

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.

Lysosomal‐associated transmembrane protein 4B regulates ceramide‐induced exosome release

“…9,22 In addition, in our previous study, we found that Cer extracted from the higher plant Amorphophallus konjac increased exosome release from neuroblastoma SH-SY5Y cells. 39 Furthermore, oral administration of plant Cer to human APP SweInd transgenic mice resulted in increased neuronal exosomes in the blood and brain, as well as decreased Aß levels and amyloid depositions in the brain. 39 Here, we verified that Cer addition moderates the abnormal accumulation of Aß in cells through LAPTM4B ( Figure 6), suggesting that Cer/LAPTM4Bdependent vesicle trafficking and exosomal efflux can modulate cellular Aß levels.…”

“…39 Furthermore, oral administration of plant Cer to human APP SweInd transgenic mice resulted in increased neuronal exosomes in the blood and brain, as well as decreased Aß levels and amyloid depositions in the brain. 39 Here, we verified that Cer addition moderates the abnormal accumulation of Aß in cells through LAPTM4B ( Figure 6), suggesting that Cer/LAPTM4Bdependent vesicle trafficking and exosomal efflux can modulate cellular Aß levels. The expression level and activity of acid ceramidase are disrupted in the brains of AD patients.…”

Blood-brain barrier permeability analysis of plant ceramides

“…The pathology of AD begins with the formation of amyloid plaques (senile plaques) due to the accumulation of amyloid-β protein (Aβ) in the brain [ 18 , 19 ]. In a previous study, we reported that oral administration of GlcCer extracted from Amorphophallus Konjac to an AD mouse model markedly decreased Aβ accumulation, suppressed amyloid deposition in the brain, and improved cognitive ability in a Y-maze learning task [ 20 , 21 ]. In addition, after plant GlcCer administration, levels of neuronal exosomes, a type of extracellular vesicle (EV), were elevated in blood and brain tissues [ 21 ].…”

“…In a previous study, we reported that oral administration of GlcCer extracted from Amorphophallus Konjac to an AD mouse model markedly decreased Aβ accumulation, suppressed amyloid deposition in the brain, and improved cognitive ability in a Y-maze learning task [ 20 , 21 ]. In addition, after plant GlcCer administration, levels of neuronal exosomes, a type of extracellular vesicle (EV), were elevated in blood and brain tissues [ 21 ]. Our previous studies demonstrated that neuronal exosomes promote Aβ clearance, and plant ceramides enhance production of exosomes in neuronal cells [ 22 , 23 ], suggesting that plant ceramides might affect exosome production within the brain.…”

Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences

“…However, as a consequence, this might implicate a role for EVs in the formation of extracellular Aβ plaques. Mechanistically, the interaction between Aβ and the surface of the EVs was shown to be mediated by glycosphingolipids [ 48 , 54 , 55 , 56 ] and the cellular prion protein (PrP C ) [ 49 ] present on the EV membrane. Furthermore, it was shown that the hippocampal administration of EVs isolated from N2a cells [ 54 ] or mouse primary neurons [ 55 ] in APP SweInd mice causes a reduction in total Aβ levels and the amount of thioflavin-S positive plaques, which was attributed to an EV-associated Aβ uptake by microglia [ 54 ].…”