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The Lipid Peroxidation Product 4‐Hydroxynonenal Inhibits Neurite Outgrowth, Disrupts Neuronal Microtubules, and Modifies Cellular Tubulin
Author(s) -
Neely M. D.,
Sidell K. R.,
Graham D. G.,
Montine T. J.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0722323.x
Subject(s) - 4 hydroxynonenal , neurite , lipid peroxidation , microtubule , tubulin , microbiology and biotechnology , chemistry , cytoskeleton , oxidative stress , biochemistry , biology , in vitro , cell
Oxidative stress is believed to be an important factor inthe development of age‐related neurodegenerative diseases such as Alzheimer'sdisease (AD). The CNS is enriched in polyunsaturated fatty acids and istherefore particularly vulnerable to lipid peroxidation. Indeed, accumulationof lipid peroxidation products has been demonstrated in affected regions inbrains of AD patients. Another feature of AD is a change in neuronalmicrotubule organization. A possible causal relationship between lipidperoxidation products and changes in neuronal cell motility and cytoskeletonhas not been investigated. We show here that 4‐hydroxy‐2( E )‐nonenal (HNE), a major product of lipid peroxidation, inhibits neurite outgrowth and disrupts microtubules in Neuro 2A cells. The effect of HNE on microtubules was rapid, being observed after incubation times as short as 15 min. HNE can react with target proteins by forming either Michael adducts or pyrrole adducts. 4‐Oxononanal, and HNE analogue that can form only pyrrole adducts but not Michael adducts, had no effect on the microtubules. This suggests that the HNE‐induced disruption of microtubules occurs via Michael addition. We also show that cellular tubulin is one of the major proteins modified by HNE and that the HNE adduction to tubulin occurs via Michael addition. Inhibition of neurite outgrowth, disruption of microtubules, and tubulin modification were observed at pathologically relevant HNE concentrations and were not accompanied by cytotoxicity. Our results show that these are proximal effects of HNE that may contribute to cytoskeletal alterations that occur in AD.