Targeting Ras Activity Prevented Amyloid Beta-Induced Aberrant Neuronal Cell Cycle Re-Entry and Death

Abstract

Several studies suggest that soluble Amyloid β (Aβ) oligomer-induced aberrant neuronal cell cycle re-entry is the initial trigger for a significant part of the neuronal degeneration and loss in Alzheimer's disease (AD). In this study, we investigated the role of Ras, which is a well-known protooncoprotein, in soluble Aβ oligomer-induced aberrant neuronal cell cycle activation and subsequent cell loss using retinoic acid differentiated human SH-SY5Y neuroblastoma cells as model system. In line with previous literature, we showed that in vitro preparations of soluble Aβ42 oligomers triggered cell cycle activation but not cell proliferation. As a new finding, we showed that Farnesylthiosalicylic acid (FTS), a specific chemical Ras inhibitor, prevented soluble Aβ42 oligomer preparation-induced cell cycle activation. Moreover, we showed that the expression of dominant negative mutant H-Ras (S17N) prevented soluble Aβ42 oligomer preparation-induced cell cycle activation, confirming the specific role of Ras in this pathway. As a possible better mimic of the situation in the AD brain, we prepared soluble oligomers from Aβ42 : Aβ40 (3:7) peptide mixture and showed that this oligomer preparation similarly induced cell cycle activation which was also inhibited by the Ras inhibitor. Finally, we showed that FTS prevented soluble Aβ42 oligomer preparationinduced cell death in our retinoic acid differentiated SH-SY5Y cells. Overall, our results strongly suggest that Ras activity is required for soluble Aβ oligomer-induced aberrant neuronal cell cycle reentry and subsequent neuronal loss, which are considered important mechanisms in AD pathogenesis.

Dexmedetomidine attenuates the toxicity of β‑amyloid on neurons and astrocytes by increasing BDNF production under the regulation of HDAC2 and HDAC5

“…Aβ-induced neurotoxicity and neuroinflammation play an important role in AD pathogenesis. Aβ causes neuronal cell death in the development of AD, resulting in cognitive and behavioral deficits (28,29). The neuronal cell death is closely related to Aβ-induced oxidative stress and consequent activation of pro-apoptosis signaling, because antioxidative substances and inhibition of apoptosis signaling, alone or in combination, prevent the cell death (30)(31)(32).…”

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“…Since RAS activity is associated with neurodegenerative pathways, FTS acts as a chemical RAS inhibitor, which was developed and tested as a cancer drug, and its role in degenerative diseases such as AD has been increasingly studied recently 13,17. Here, we determined that FTS attenuated Aβ-induced ERK, CREB hyperphosphorylation by inhibiting RAS.…”

“…Mitogenic overstimulation of neurons is an important cause of abnormal activation of the cell cycle and subsequent cell death,12 which is an important component of the pathogenesis of AD and other degenerative diseases 37. Aβ 42 oligomer preparation could also induce cell cycle activation and subsequent neuronal loss by activating RAS 13. RAS signaling pathway is involved in synaptic plasticity and memory formation 38.…”

“…Mitogenic overstimulation of neurons led to the dedifferentiation of cells, causing abnormal entry of the cell cycle, ultimately causing neurocyte death 12. In AD, Aβ oligomer-induced abnormal cell cycle activation and subsequent cell loss may be associated with RAS 13. RAS has to be anchored to the inner leaf of the cell membrane through farnesylation to receive and transmit signals 14.…”

“…FTS has been shown to inhibit RAS-dependent cell growth 17. In vitro studies have shown that FTS can organize abnormal cell cycle re-entry induced by soluble Aβ oligomers 13. Recently, a study has shown that the inhibition of RAS by FTS could enhance NMDAr-dependent long-term potentiation by increasing Src activity, resulting in enhanced spatial memory 18.…”