title: Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation.
abstract: Alzheimer's disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloid β-peptides (Aβ) and intracellular deposits of hyperphosphorylated tau (phospho-tau) protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via Aβ generation. Enhanced levels of ceramides directly increase Aβ through stabilization of β-secretase, the key enzyme in the amyloidogenic processing of Aβ precursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar Aβ induces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS), cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs). This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with Aβ in the cascade of events ending in neuronal degeneration.
authors.affiliation: Laboratory for Molecular Neuropharmacology, Division of Molecular Medicine, Rudjer Bošković Institute, 10000 Zagreb, Croatia ; Department of Psychology, Croatian Catholic University, 10000 Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Jazvinšćak Jembrek
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.affiliation: Department for Neuroscience, Croatian Institute for Brain Research, University of Zagreb Medical School, 10000 Zagreb, Croatia.
authors.forename: Goran
authors.initials: G
authors.lastname: Šimić
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002518:Ceramides / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress
chemical_list: D016229:Amyloid beta-Peptides; D002518:Ceramides