Modifications of Phosphorylated Tau Immunoreactivity Linked to Excitotoxicity in Neuronal Cultures
Glutamate is one of the major excitatory neurotransmitters in the human brain (Fonnum 1984) but is also a potent neurotoxin producing in vitro and in vivo neuronal degradation and death (Meldrum and Garthwaite 1991). Three types of post-synaptic receptors are described: N-Methyl D aspartate, AMPA/Kainate, and metabotropic according to their principal pharmacological agonists. A large variety of molecules can activate these three post-synaptic receptors (Seeburg 1993). Glutamate has been implicated in the pathophysiology of many neurodegenerative disorders both acute, such as stroke and hypoglycemia (Simon et al. 1984; Wieloch 1985), and chronic, such as amyotrophic lateral sclerosis (Couratier et al. 1993), Parkinson’s disease (Turski et al. 1991), Huntington’s disease (Young et al. 1988), AIDS dementia complex (Lipton et al. 1991) and Alzheimer’s disease (Koh et al. 1990; Kowall and Beal 1991; Mattson et al. 1992). Glutamate is also able to produce an intracellular signal transduction into neurons leading to protein phosphorylations (Scholz and Palfrey 1991). Tau is a microtubule-associated protein which favours microtubule polymerisation and stabilisation (Kosik 1993). One of the major neuropathological hallmarks of Alzheimer’s disease is neurofibrillary tangles (NFT) associated with neuronal degeneration. NFT are composed of paired helical neurofilaments (PHF). Tau is one of the principal constituents of PHF but PHF tau is abnormally phosphorylated (Brion et al. 1991; Goedert 1993; Lee and Trojanowski 1992). The goal of the following experiments was to detect changes in tau immunoreactivity observed in neuronal cultures after glutamate exposure. We used a new monoclonal antibody, AT8 (provided by Innogenetics), raised against an abnormally phophorylated tau site at serine 202. Immunocytochemistry with confocal laser microscopy and immunoblot studies were carried out in these experiments.
KeywordsDementia Selenium Serine Neurol Progesterone
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