Amyloid β1-42 (Aβ1-42) Induces the CDK2-Mediated Phosphorylation of Tau through the Activation of the mTORC1 Signaling Pathway While Promoting Neuronal Cell Death

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment and memory loss. Amyloid β1-42 (Aβ) and hyper-phosphorylation of microtubule-associated protein tau have been considered as major histological features in AD. However, the mechanism of how Aβ induces the hyper-phosphorylation of tau remains to be clarified. In the present study, we investigated the underlying cellular mechanisms of Aβ with regard to the cell cycle regulatory protein-mediated phosphorylation of tau in promoting neuronal cell death. The oligomer Aβ (5 μM) significantly increased the level of caspase 3 cleavage and has the ability to induce cytotoxicity in human neuroblastoma SK-N-MC cells. Aβ induced the degree of extracellular calcium influx via the L-type channel to facilitate the production of reactive oxygen species (ROS). Aβ 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 Aβ 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. Aβ 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 Aβ is highly susceptible to the mTORC1 signaling pathway. These results demonstrate that Aβ 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.

Molecular crosstalk between cancer and neurodegenerative diseases

“…Conversely, parkin overexpression retarded the cyclin E accumulation in cultured neurons treated with excitotoxin, and protected the neurons from the kainate-induced excitotoxicity [182]. Cyclin E expression is also related to AD [183][184][185], for example, expression of cyclin E in the brain induced cell cycle activation and Cyclin D1, associated with CDK4 and CDK6, modulates the entry from quiescence (G 0 ) to the G1 phase of the cell cycle, and is also linked to the progression of neurodegeneration. Cyclin E plays a role in the initiation of DNA replication at the G1/S checkpoint, and also causes neurodegeneration in the postmitotic neurons.…”

Checkpoint signaling abrogation after cell cycle reentry reveals that differentiated neurons are mitotic cells

“…This possibility is supported by previous reports (Cicero and Herrup, 2005). In extension, Cdk5 overactivation, which is associated to neurodegenerative processes (Su and Tsai, 2011), is likely concomitant to the release Cyclin E. Hence, we suggest that pathophysiological events linked to neurotoxic Cdk5 activity can be alternatively or complementarily accounted by Cdk2 activation (Lee et al, 2017). In support, Cdk5 deregulation is associated to aberrant tau phosphorylation (Su and Tsai, 2011) and Cyclin E/Cdk2 can also phosphorylate tau (Schmetsdorf et al, 2009).…”

“…25, 2018; 6 neurons, which was suggestive of neuronal death. This was not surprising, as Cyclin E is consistently associated to apoptosis during aberrant cell-cycle re-entry in neurons (Absalon et al, 2013;Copani et al, 1999;Lee et al, 2017;Schwartz et al, 2007;VeasPérez de Tudela et al, 2015;Verdaguer et al, 2002). Thus, we assessed if t1EK2 was inducing apoptosis by active caspase-3 immunolabeling.…”

“…25, 2018; 4 E is likely central in aberrant neuronal cell-cycle re-entry. Along these lines, upregulation of Cyclin E is reported in AD (Hoozemans et al, 2002;Nagy et al, 1997) and in models of aberrant neuronal cell-cycle re-entry in response to amyloid β (Aβ) (Copani et al, 1999;Lee et al, 2017), excitotoxicity induced by glutamate (Veas-Pérez de Tudela et al, 2015) and kainic acid (Verdaguer et al, 2002), Parkin deficiency (Staropoli et al, 2003), treatment with Parkinsonian mimetic 1-Methyl-4-phenylpyridinium (MPP + ) (Harbison et al, 2011), toxic concentrations of hydrogen peroxide (Schwartz et al, 2007), and the overexpression of the AD-associated mir-26b (Absalon et al, 2013). However, it is yet to be determined whether Cyclin E deregulation can induce neuronal cell-cycle re-entry as it does in mitotic cells and whether it has comparable consequences.…”

“Olfactory Three-Needle” Enhances Spatial Learning and Memory Ability in SAMP8 Mice

“…Aberrant phosphorylation of tau protein can cause changes in synaptic structure and function, synaptic loss, and neurotransmitter inactivation [27] and induce learning and memory impairment and loss of synaptic function in transgenic model mice [28]. A recent report has shown that the Aβ polypeptide fragments were involved in promoting the high phosphorylation of tau protein through mTOR signaling pathway to induce nerve apoptosis [29], while some studies have shown that the p38 MAPK signaling pathway may also contribute to the regulation of tau protein phosphorylation in the hippocampus [30,31]. In our study, the neurons with high expression of P-p38 and P-tau were observed in the hippocampus CA1, CA3, and GD areas of SAMP8 mice.…”