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Ceramides in Alzheimer’s Disease: key mediators of neuronal apoptosis induced by oxidative stress and Aβ accumulation

Jazvinšćak Jembrek, Maja; Hof, Patrick R.; Šimić, Goran (2015) Ceramides in Alzheimer’s Disease: key mediators of neuronal apoptosis induced by oxidative stress and Aβ accumulation. Oxidative Medicine and Cellular Longevity, 2015 . pp. 346783-1. ISSN 1942-0900

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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.

Item Type: Article
Uncontrolled Keywords: ceramides; oxidative stress; Aβ, apoptosis; Alzheimer's disease
Subjects: BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Pharmacology
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Neuroscience
Divisions: Division of Molecular Medicine
Projects:
Project titleProject leaderProject codeProject type
Stres, GABA-A receptori i mehanizmi djelovanja neuropsihofarmaka[258591] Dubravka Švob Štrac098-0000000-2448MZOS
Depositing User: Maja Jazvinšćak Jembrek
Date Deposited: 26 May 2015 12:37
Last Modified: 26 May 2015 12:37
URI: http://fulir.irb.hr/id/eprint/1968
DOI: 10.1155/2015/346783

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