Amyloid ß1-42 (Aß1-42) Induces the CDK2-Mediated Phosphorylation of Tau through the Activation of the mTORC1 Signaling Pathway While Promoting Neuronal Cell Death.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment and memory loss. Amyloid ß1-42 (Aß) and hyper-phosphorylation of microtubule-associated protein tau have been considered as major histological features in AD. However, the mechanism of how Aß induces the hyper-phosphorylation of tau remains to be clarified. In the present study, we investigated the underlying cellular mechanisms of Aß with regard to the cell cycle regulatory protein-mediated phosphorylation of tau in promoting neuronal cell death. The oligomer Aß (5 µM) significantly increased the level of caspase 3 cleavage and has the ability to induce cytotoxicity in human neuroblastoma SK-N-MC cells. Aß induced the degree of extracellular calcium influx via the L-type channel to facilitate the production of reactive oxygen species (ROS). Aß signaling through ROS production is uniquely mediated by the activation of PI3K/Akt, which is in turn required for mammalian target of rapamycin complex 1 (mTORC1) phosphorylation. mTORC1 activated by Aß further increased the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a binding protein (4E-BP1) and p70S6K1 to stimulate the HIF1α synthesis responsible for the induction of cyclinD1/cyclin-dependent kinase 4 (CDK4) and cyclinE/CDK2, whereas it significantly attenuated the activation of autophagy. Aß distinctively induced the CDK2-mediated phosphorylation of tau, which is responsible for microtubule destabilization in promoting neuronal apoptosis. In mouse hippocampal primary neurons, the apoptotic cell death induced by Aß is highly susceptible to the mTORC1 signaling pathway. These results demonstrate that Aß efficiently stimulates the mTORC1 signaling pathway to facilitate HIF1α synthesis and autophagy inhibition to promote the expression of cell cycle regulatory proteins, during which CDK2 uniquely stimulates tau phosphorylation for microtubule destabilization-mediated neuronal apoptosis.

Relationship Between ß-Amyloid and Mitochondrial Dynamics.

Mitochondria as dynamic organelles undergo morphological changes through the processes of fission and fusion which are major factors regulating their functions. A disruption in the balance of mitochondrial dynamics induces functional disorders in mitochondria such as failed energy production and the generation of reactive oxygen species, which are closely related to pathophysiological changes associated with Alzheimer's disease (AD). Recent studies have demonstrated a relationship between abnormalities in mitochondrial dynamics and impaired mitochondrial function, clarifying the effects of morphofunctional aberrations which promote neuronal cell death in AD. Several possible signaling pathways have been suggested for a better understanding of the mechanism behind the key molecules regulating mitochondrial morphologies. However, the exact machinery involved in mitochondrial dynamics still has yet to be elucidated. This paper reviews the current knowledge on signaling mechanisms involved in mitochondrial dynamics and the significance of mitochondrial dynamics in controlling associated functions in neurodegenerative diseases, particularly in AD.

Aß-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis.

Mitochondrial dysfunction is known as one of causative factors in Alzheimer's disease (AD), inducing neuronal cell death. Mitochondria regulate their functions through changing their morphology. The present work was undertaken to investigate whether Amyloid ß (Aß) affects mitochondrial morphology in neuronal cells to induce apoptosis. Aß treatment induced not only the fragmentation of mitochondria but also neuronal apoptosis in association with an increase in caspase-9 and -3 activity. Calcium influx induced by Aß up-regulated the activation of Akt through CaMKII resulting in changes to the phosphorylation level of Drp1 in a time-dependent manner. Translocation of Drp1 from the cytosol to mitochondria was blocked by CB-124005 (an Akt inhibitor). Recruitment of Drp1 to mitochondria led to ROS generation and mitochondrial fission, accompanied by dysfunction of mitochondria such as loss of membrane potential and ATP production. ROS generation and mitochondrial dysfunction by Aß were attenuated when treated with Mdivi-1, a selective Drp1 inhibitor. Furthermore, the sustained Akt activation induced not only the fragmentation of mitochondria but also the activation of mTOR, eventually suppressing autophagy. Inhibition of autophagic clearance of Aß led to increased ROS levels and aggravating mitochondrial defects, which were blocked by Rapamycin (an mTOR inhibitor). In conclusion, sustained phosphorylation of Akt by Aß directly activates Drp1 and inhibits autophagy through the mTOR pathway. Together, these changes elicit abundant mitochondrial fragmentation resulting in ROS-mediated neuronal apoptosis.

Regulation of Stem Cell Fate by ROS-mediated Alteration of Metabolism.

Stem cells have attracted much attention due to their distinct features that support infinite self-renewal and differentiation into the cellular derivatives of three lineages. Recent studies have suggested that many stem cells both embryonic and adult stem cells reside in a specialized niche defined by hypoxic condition. In this respect, distinguishing functional differences arising from the oxygen concentration is important in understanding the nature of stem cells and in controlling stem cell fate for therapeutic purposes. ROS act as cellular signaling molecules involved in the propagation of signaling and the translation of environmental cues into cellular responses to maintain cellular homeostasis, which is mediated by the coordination of various cellular processes, and to adapt cellular activity to available bioenergetic sources. Thus, in this review, we describe the physiological role of ROS in stem cell fate and its effect on the metabolic regulation of stem cells.