The novel multitarget iron chelating and propargylamine drug M30 affects APP regulation and processing activities in Alzheimer's disease models. (1st September 2017)

• Record Type: Journal Article
• Authors: Amit, Tamar; Bar-Am, Orit; Mechlovich, Danit; Kupershmidt, Lana; Youdim, Moussa B.H.; Weinreb, Orly
• Is Part Of: Neuropharmacology. Volume 123(2017)
• Page Start: 359
• Page End: 367
• Publication Date: 2017-09-01
• Subjects: Alzheimer's disease -- APP processing/regulation -- Amyloid β -- Iron chelation -- Propargyl moiety; AChEIs Acetyl cholinesterase inhibitors -- ADAM10 a disintegrin and metalloproteinase domain 10 -- Aβ amyloid β -- APP amyloid precursor protein -- APOE4 apolipoprotein E isoform E4 -- β-CTF β-C-terminal fragment -- BACE1 β-site amyloid cleavage enzyme 1 -- BDNF brain-derived neurotrophic factor -- CNS central nervous system -- CDK5 cyclin-dependent kinase 5 -- DFO desferrioxamine -- EGCG epigallocatechin gallate -- GDNF glial cell line derived neurotrophic factor -- Glut glucose transporter -- GSK3β glycogen synthase kinase 3β -- HFE Haemochromatosis -- HO-1 heme oxygenase -- HFD high fat diet -- HIF-1 hypoxia inducible factor-1 -- IRPs iron regulatory proteins -- MRI magnetic resonance imaging -- MAPK mitogen-activated protein kinase -- MAO monoamine oxidase -- NFTs neurofibrillary tangles -- PS1 presenilin 1 -- AKT protein kinase B -- PKC protein kinase C -- Tg transgenic -- T2DM type 2 diabetes mellitus -- VEGF vascular endothelial factor; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.05.026
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: In many of the neurodegenerative diseases, such as Alzheimer's disease (AD) and AD-related disorders, as well as in the regular ageing process, excessive generation of oxidative stress (OS) and accumulation of iron levels and deposition have been observed in specific affected-brain regions and thus, regarded as contributing factors to the pathogenesis of the diseases. In AD, iron promotes amyloid β (Aβ) neurotoxicity by producing free radical damage and OS in brain areas affected by neurodegeneration, presumably by facilitating the aggregation of Aβ. In addition, it was shown that iron modulates intracellular levels of the holo amyloid precursor protein (APP) by iron-responsive elements (IRE) RNA stem loops in the 5′ untranslated region (5′UTR) of the APP transcript. As a consequence of these observations, iron chelation is one of the major new therapeutic strategies for the treatment of AD. This review describes the benefits and importance of the multimodal brain permeable chimeric iron-chelating/propargylamine drug M30, concerning its neuroprotective/neurorestorative inter-related activities relevant of the pathological features ascribed to AD, with a special focus on the effect of the drug on APP regulation and processing. Highlights: M30; a multimodal brain permeable chimeric iron-chelating/propargylamine drug. M30 exerts neuroprotective/neurorestorative in Alzheimer's disease models. M30 possesses effects on APP regulation and processing.