The glial glutamate transporter, GLT‐1, is oxidatively modified by 4‐hydroxy‐2‐nonenal in the Alzheimer's disease brain: the role of Aβ1–42

Abstract

Glutamate transporters are involved in the maintenance of synaptic glutamate concentrations. Because of its potential neurotoxicity, clearance of glutamate from the synaptic cleft may be critical for neuronal survival. Inhibition of glutamate uptake from the synapse has been implicated in several neurodegenerative disorders. In particular, glutamate uptake is inhibited in Alzheimer's disease (AD); however, the mechanism of decreased transporter activity is unknown. Oxidative damage in brain is implicated in models of neurodegeneration, as well as in AD. Glutamate transporters are inhibited by oxidative damage from reactive oxygen species and lipid peroxidation products such as 4‐hydroxy‐2‐nonenal (HNE). Therefore, we have investigated a possible connection between the oxidative damage and the decreased glutamate uptake known to occur in AD brain. Western blots of immunoprecipitated HNE‐immunoreactive proteins from the inferior parietal lobule of AD and control brains suggest that HNE is conjugated to GLT‐1 to a greater extent in the AD brain. A similar analysis of beta amyloid (Aβ)‐treated synaptosomes shows for the first time that Aβ1–42 also increases HNE conjugation to the glutamate transporter. Together, our data provide a possible link between the oxidative damage and neurodegeneration in AD, and supports the role of excitotoxicity in the pathogenesis of this disorder. Furthermore, our data suggests that Aβ may be a possible causative agent in this cascade.

Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer’s disease

“…As shown in Fig. 2, the antibodies for the three glutamate transporters detected specific bands on Western blot, similar to those reported in the literature for rat and human brain [29,46]. The glutamate transporters bands were completely abolished when antibodies were pre-adsorbed with 50 M synthetic GLAST, GLT-1 and EAAC1 oligopeptides (data not shown).…”

Redox regulation of cellular stress response in multiple sclerosis

“…As shown, protein carbonyls were found at a significantly (P < 0.05) higher level in the CSF of MS patients than in control subjects. Furthermore, one measure of oxidative marker is lipid oxidation, indexed by HNE [25,26], which can also occur in brain under oxidative stress [27]. HNE, formed from arachidonic acid or other unsaturated fatty acids following free radical attack, binds by Michael addition to proteins, particularly at cysteine, histidine, or lysine residues [27].…”

In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

“…HNE is a highly reactive product of arachidonic acid metabolism that is believed to interfere with normal cellular functions [3]. During oxidative stress several lipid peroxidation products are formed, including HNE, one of the most abundant and toxic lipid-derived aldehydes, and which can induce oxidative stress [69,70]. Lipid peroxidation products such as HNE and acrolein are known to cause damage to biomembranes, proteins and other biomolecules in AD brain [70][71][72].…”

“…During oxidative stress several lipid peroxidation products are formed, including HNE, one of the most abundant and toxic lipid-derived aldehydes, and which can induce oxidative stress [69,70]. Lipid peroxidation products such as HNE and acrolein are known to cause damage to biomembranes, proteins and other biomolecules in AD brain [70][71][72]. These alkenals form an immediate substrate for GSH [73] and these lipid peroxidation products are known to be involved in apoptosis, which can be initiated as a consequence of GSH depletion [74].…”