Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation. (24th May 2015)

• Record Type: Journal Article
• Authors: Jazvinšćak Jembrek, Maja; Hof, Patrick R.; Šimić, Goran
• Other Names: Curcio Manuela Academic Editor.
• Is Part Of: Oxidative medicine and cellular longevity. Volume 2015(2015)
• Publication Date: 2015-05-24
• Subjects: Oxidative stress -- Periodicals; Cells -- Aging -- Periodicals; Cells -- Aging; Oxidative stress; Oxidative Stress -- Periodicals; Cell Aging -- Periodicals; Periodicals; 611.0181
• DOI: 10.1155/2015/346783
• Languages: English
• ISSNs: 1942-0900

Abstract

Abstract : Alzheimer's disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloid β -peptides (A β ) 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 A β generation. Enhanced levels of ceramides directly increase A β through stabilization of β -secretase, the key enzyme in the amyloidogenic processing of A β precursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar A β 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 A β in the cascade of events ending in neuronal degeneration.