scholarly journals Casein Kinase 2 dependent phosphorylation of eIF4B regulates BACE1 expression in Alzheimer’s disease

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Barbara Bettegazzi ◽  
Laura Sebastian Monasor ◽  
Serena Bellani ◽  
Franca Codazzi ◽  
Lisa Michelle Restelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Activity ◽  
Neurodegenerative Disorder ◽  
Brain Slices ◽  
Casein Kinase ◽  
Casein Kinase 2 ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Bace1 Expression

AbstractAlzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

2021 ◽  
Vol 14 (668) ◽  
pp. eabc5429
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Postmortem Brain Tissue ◽  
Phosphorylated Eif2α

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

scholarly journals MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation

Brain ◽  
2018 ◽  
Vol 142 (1) ◽  
pp. 176-192 ◽  
Author(s):  
Bing-Lin Zhu ◽  
Yan Long ◽  
Wei Luo ◽  
Zhen Yan ◽  
Yu-Jie Lai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Translation Initiation Factor ◽  
Precursor Protein ◽  
Initiation Factor ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Model Of Alzheimer’S Disease

AbstractMMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer’s disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (β-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5′ untranslated region (5′UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5′UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer’s disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-β precursor protein processing, amyloid-β load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer’s disease, via the translational regulation of BACE1.

scholarly journals The decreased level of casein kinase 2 in brain cortex of schizophrenic and Alzheimer's disease patients

FEBS Letters ◽  
1991 ◽  
Vol 279 (1) ◽  
pp. 55-57 ◽  
Author(s):  
M.V. Aksenova ◽  
G.Sh. Burbaeva ◽  
K.V. Kandror ◽  
D.V. Kapkov ◽  
A.S. Stepanov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Cortex ◽  
Casein Kinase ◽  
Casein Kinase 2

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity and memory in mouse models of Alzheimer’s disease

2020 ◽  
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Mouse Models ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Long Term Memory

AbstractNeuronal protein synthesis is essential for long-term memory consolidation. Conversely, dysregulation of protein synthesis has been implicated in a number of neurodegenerative disorders, including Alzheimer’s disease (AD). Several types of cellular stress trigger the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α-P). This leads to attenuation of cap-dependent mRNA translation, a component of the integrated stress response (ISR). We show that AD brains exhibit increased eIF2α-P and reduced eIF2B, key components of the eIF2 translation initiation complex. We further demonstrate that attenuating the ISR with the small molecule compound ISRIB (ISR Inhibitor) rescues hippocampal protein synthesis and corrects impaired synaptic plasticity and memory in mouse models of AD. Our findings suggest that attenuating eIF2α-P-mediated translational inhibition may comprise an effective approach to alleviate cognitive decline in AD.

scholarly journals Phosphorylation of Maize Eukaryotic Translation Initiation Factor 5A (eIF5A) by Casein Kinase 2

2009 ◽  
Vol 285 (9) ◽  
pp. 6217-6226 ◽  
Author(s):  
Maja Łebska ◽  
Arkadiusz Ciesielski ◽  
Lidia Szymona ◽  
Luiza Godecka ◽  
Elżbieta Lewandowska-Gnatowska ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Casein Kinase ◽  
Casein Kinase 2 ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

scholarly journals The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer’s Disease

2021 ◽  
Vol 22 (6) ◽  
pp. 3136
Author(s):  
Jacques Hugon ◽  
Claire Paquet
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Translation Initiation Factor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Mitogen Activated Protein

Neuropathological lesions in Alzheimer’s disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.

scholarly journals Limited Effects of aneIF2αS51AAllele on Neurological Impairments in the 5xFAD Mouse Model of Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Katharina Paesler ◽  
Kan Xie ◽  
Moritz M. Hettich ◽  
Magdalena E. Siwek ◽  
Devon P. Ryan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Translational Control ◽  
Behavioral Assessment ◽  
Epileptic Activity ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Model Of Alzheimer’S Disease ◽  
Eeg Recordings ◽  
5Xfad Mice

Alzheimer’s disease (AD) has been associated with increased phosphorylation of the translation initiation factor 2α(eIF2α) at serine 51. Increased phosphorylation of eIF2αalters translational control and may thereby have adverse effects on synaptic plasticity, learning, and memory. To analyze if increased levels of p-eIF2αindeed promote AD-related neurocognitive impairments, we crossed 5xFAD transgenic mice with aneIF2αS51Aknock-in line that expresses the nonphosphorylatable eIF2αvarianteIF2αS51A. Behavioral assessment of the resulting mice revealed motor and cognitive deficits in 5xFAD mice that were, with the possible exception of locomotor hyperactivity, not restored by theeIF2αS51Aallele. Telemetric intracranial EEG recordings revealed no measurable effects of theeIF2αS51Aallele on 5xFAD-associated epileptic activity. Microarray-based transcriptome analyses showed clear transcriptional alterations in 5xFAD hippocampus that were not corrected by theeIF2αS51Aallele. In contrast to prior studies, our immunoblot analyses did not reveal increased levels of p-eIF2αin the hippocampus of 5xFAD mice, suggesting that elevated p-eIF2αlevels are not a universal feature of AD models. Collectively, our data indicate that 5xFAD-related pathologies do not necessarily require hyperphosphorylation of eIF2αto emerge; they also show that heterozygosity for the nonphosphorylatableeIF2αS51Aallele has limited effects on 5xFAD-related disease manifestations.

Sign in / Sign up

Export Citation Format

Share Document