Abstract
Epidermal growth factor receptors are widely expressed in various tissues, including the brain, and play an important role in the regulation of such biological processes as proliferation, cell migration and death, etc. This study aimed to study the involvement of the cell survival-related signaling pathways (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 senescence compared to the wild type mice (FVB/N strain). In the hypothalamic supraoptic and paraventricular nuclei, expression of the anti-apoptotic protein survivin was determined by immunohistochemistry, while expression of proteins of the cytokine-dependent cascades (FASL, TNF-alpha) and protein members of the cell survival-related signaling pathways (phosphorylated AKT, ERK, NF-kB) was assayed by Western blotting. It was found that in FVB/N mice the AKT and ERK cascades do not contribute significantly to neuronal senescence, 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 resistance to apoptosis during aging is ensured by a combination of different cell survival-related signaling pathways: the ERK cascade 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.
Published Version
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