Toxic neuronal apoptosis and modifications of tau and APP gene and proteinexpressions

The causes and the mechanisms of neuronal death in Alzheimer's disease are not elucidated, although some new insights have been proposed over the past years, including free-radical toxicity, beta-amyloid toxicity, excitotoxic ity, and disturbed cellular calcium metabolism. Some authors have also poin ted out that apoptosis could play a role in neuronal degeneration, but it i s still largely debated. Here, we review some recent data linking the induc tion of experimental neuronal apoptosis in vitro and the molecular patholog y of the tau protein and amyloid precursor protein (APP). In cultures expos ed to mild glutamate toxicity, tau mRNA expression, not beta-actin, is enha nced in stressed neurons. The Guam cycad toxin metabolite methylazoxymethan ol also produces an increase of <it>tau</it> gene transcription that exacer bates changes induced by glutamate. In serumdeprived cultures or glutamate- exposed cultures, neurons committed to apoptosis have a reduced <it>tau</it > gene expression, whereas resistant neurons display a stable or even augme nted tau mRNA expression accompanied by a persistent tau phosphorylation ne ar serine 202. In the same conditions, stressed neurons produce membrane bl ebbings strongly immunopositive for APP and putative amyloidogenic fragment s that are subsequently released in the extracellular space. Experimental a poptosis in neurons can recapitulate tau and APP modifications that could b e associated with a selective vulnerability and a progression of cellular d egeneration along the neuronal network.