Pathological apoptosis in the developing brain

Abstract

More than half of the initially-formed neurons are deleted in certain brain regions during normal development. This process, whereby cells are discretely removed without interfering with the further development of remaining cells, is called programmed cell death (PCD). The term apoptosis is used to describe certain morphological manifestations of PCD. Many of the effectors of this developmental cell death program are highly expressed in the developing brain, making it more susceptible to accidental activation of the death machinery, e.g. following hypoxia-ischemia or irradiation. Recent evidence suggests, however, that activation and regulation of cell death mechanisms under pathological conditions do not exactly mirror physiological, developmentally regulated PCD. It may be argued that the conditions after e.g. ischemia are not even compatible with the execution of PCD as we know it. Under pathological conditions cells are exposed to various stressors, including energy failure, oxidative stress and unbalanced ion fluxes. This results in parallel triggering and potential overshooting of several different cell death pathways, which then interact with one another and result in complex patterns of biochemical manifestations and cellular morphological features. These types of cell death are here called "pathological apoptosis," where classical hallmarks of PCD, like pyknosis, nuclear condensation and caspase-3 activation, are combined with non-PCD features of cell death. Here we review our current knowledge of the mechanisms involved, with special focus on the potential for therapeutic intervention tailored to the needs of the developing brain.

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

“…In this study, caffeine increased GSK3β phosphorylation at Ser9; this regulation was controlled by PKA. In normal cells, constitutively active GSK3β negatively regulates the proto-oncogenic protein, β-catenin, via phosphorylation-induced degradation, limiting its expression (Blomgren et al, 2007). Interestingly, in this study, despite an induction of GSK3β phosphorylation (at Ser9), we observed no increase in β-catenin expression after caffeine treatment.…”

“…In previous studies, regulation of p21 expression and Rb phosphorylation were shown to be responsible for cell cycle arrest in the G 0 /G 1 phase in glioma cells (Choi et al, 2008;Tsai et al, 2006). GSK3 is a multifunctional serine/threonine kinase that reg β ulates various cellular pathways involved in the cell cycle, proliferation, differentiation, and apoptosis (Blomgren et al, 2007;He et al, 2003;Miyashita et al, 2009). GSK3β activity is negatively regulated by phosphorylation on Ser9 by Akt, PKA, and PKC (Blomgren et al, 2007).…”

“…GSK3 is a multifunctional serine/threonine kinase that reg β ulates various cellular pathways involved in the cell cycle, proliferation, differentiation, and apoptosis (Blomgren et al, 2007;He et al, 2003;Miyashita et al, 2009). GSK3β activity is negatively regulated by phosphorylation on Ser9 by Akt, PKA, and PKC (Blomgren et al, 2007). Although the exact role of GSK3β in malignancies is still controversial due to conflicting results from different tumor models (Miyashita et al, 2009), inactivation of GSK3β is thought to contribute to the inhibition of tumor growth via cell cycle and apoptosis regulation (Doble and Woodgett, 2003;Luo, 2009).…”

Developing Postmitotic Mammalian NeuronsIn VivoLacking Apaf-1 Undergo Programmed Cell Death by a Caspase-Independent, Nonapoptotic Pathway Involving Autophagy

“…AIF has been shown to be involved in PCD during early embryogenesis (Joza et al, 2001;Cheung et al, 2006) and in injury-induced cell death in the neonatal and adult brain (Blomgren et al, 2007;Cao et al, 2007). Finally, because we show here that neuronal PCD in the absence of Apaf-1 exhibits an autophagic morphology, we also examined whether normal neuronal PCD during development is perturbed by the loss of one of the key genes involved in autophagy, ATG7 Levine and Yuan, 2005;Komatsu et al, 2006).…”

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

“…При этом форма клеточной гибели зависит от степени гипоксии-ишемии [26]: при тяжелой -некроз, при умеренной -апоптоз [18]. Активация апоптоза обу-словлена тем, что запрограммированная гибель клеток у человека в первые дни после рождения представляет собой ведущий механизм нейропластичности, поэтому максимально проявляется именно в этот период времени [27,28]. В ряде работ экспериментаторами выделен тре-тий, промежуточный, тип погибших нейронов -гибрид-ный, который в ядрах имеет признаки апоптотической гибели, а в цитоплазме -некротический тип [18,29].…”