Abstract
Epidermal growth factor receptors are widely expressed in the various tissues, including the brain, and play an important role in the regulation of such biological processes as proliferation, cell migration, cell death, etc. This study aimed to study the involvement of signaling pathways related with cell survival (AKT, ERK, NF-kB cascades) in the regulation of hypothalamic neuronal apoptosis in experimental models of physiological and pathological (HER2/neu overexpression) aging, as well as the effect of FASL and TNF-alpha cytokines on these signaling cascades. Experiments were carried out on HER2/neu transgenic mice with accelerated cellular senescence compared to the wild type mice (FVB/N strain). In the hypothalamic supraoptic and paraventricular nuclei, expression of the antiapoptotic protein survivin was determined by immunohistochemistry, while expression of proteins of the cytokine-dependent cascades (FASL, TNF-alpha) and protein members of the survival signaling pathways (phosphorylated AKT, ERK, NF-kB) was assayed by Western blotting. It was found that in FVB/N mice the AKT, ERK cascades do not play a significant role in aging, whereas activation of FAS signaling and a decrease in the NF-kB pathway activity can lead to an increased proportion of dying neurons. In HER2/neu mice, neuronal tolerance to apoptosis during aging is provided by a combination of different survival signaling pathways: the ERK cascade is activated in the supraoptic nucleus and the NF-kB and AKT cascades in the paraventricular nucleus. In addition, a suppression of FAS signaling was revealed, also leading to a low level of apoptosis.
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