scholarly journals Antagonists targeting eEF2 kinase rescue multiple aspects of pathophysiology in Alzheimer's disease model mice

2021 ◽  
Author(s):  
Nicole P Kasica ◽  
Xueyan Zhou ◽  
Xin Wang ◽  
Wenzhong P Yang ◽  
Helena R Zimmermann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
De Novo ◽  
Therapeutic Potential ◽  
Disease Model ◽  
Elongation Factor ◽  
Mrna Translation ◽  
Therapeutic Implications

It is imperative to develop novel therapeutic strategies for Alzheimer's disease (AD) and related dementia syndromes based on solid mechanistic studies. Maintenance of memory and synaptic plasticity relies on de novo protein synthesis, which is partially regulated by phosphorylation of eukaryotic elongation factor 2 (eEF2) via its kinase eEF2K. Abnormally increased eEF2 phosphorylation and impaired mRNA translation have been linked to AD. We recently reported that prenatal genetic suppression of eEF2K is able to prevent aging-related cognitive deficits in AD model mice, suggesting the therapeutic potential of targeting eEF2K/eEF2 signaling in AD. Here, we tested two structurally-distinct small-molecule eEF2K inhibitors in two different lines of AD model mice after onset of cognitive impairments. Our data revealed that treatment with eEF2K inhibitors improved AD-associated synaptic plasticity impairments and cognitive dysfunction, without altering brain amyloid (Aβ) and tau pathology. Furthermore, eEF2K inhibition alleviated AD-associated defects in dendritic spine morphology, postsynaptic density formation, protein synthesis, and dendritic polyribosome assembly. Our results may offer critical therapeutic implications for AD, and the proof-of-principle study indicates translational implication of inhibiting eEF2K for AD and related dementia syndromes.

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.

Dysregulation of Neuronal Protein Synthesis in Alzheimer’s Disease

2020 ◽  
Author(s):  
Tao Ma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Synaptic Function ◽  
Initiation Factor ◽  
Early Event ◽  
Molecular Signaling

Currently there is no effective cure or intervention available for Alzheimer’s disease (AD), a devastating neurodegenerative disease and the most common form of dementia. It is urgent to understand the basic cellular/molecular signaling mechanisms underlying AD pathophysiology to identify novel therapeutic targets and diagnostic biomarkers. Many studies indicate impaired synaptic function as a key and early event in AD pathogenesis. Mounting evidence suggests that dysregulations in mRNA translation (protein synthesis) may contribute to the development of synaptic dysfunction and cognitive defects in neurodegenerative diseases including AD. Protein synthesis happens in three phases (initiation, elongation, and termination) and is tightly controlled through regulation of multiple signaling pathways in response to various stimuli. Integral protein synthesis is indispensable for memory formation and maintenance of synaptic plasticity. Interruption of protein synthesis homeostasis can lead to impairments in cognition and synaptic plasticity. This chapter reviews recent studies supporting the idea that impaired protein synthesis is an important mechanism underlying AD-associated cognitive deficits and synaptic failure. It focuses on three signaling cascades controlling protein synthesis: eukaryotic initiation factor 2α (eIF2α), the mammalian target of rapamycin complex 1 (mTORC1), and eukaryotic elongation factor 2 (eEF2). Findings from human and animal studies demonstrating an association between dysregulation of these pathways and AD pathophysiology are summarized and discussed.

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 Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer’s Disease

2016 ◽  
Vol 54 (2) ◽  
pp. 669-678 ◽  
Author(s):  
Brenna C. Beckelman ◽  
Stephen Day ◽  
Xueyan Zhou ◽  
Maggie Donohue ◽  
Gunnar K. Gouras ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Elongation Factor

scholarly journals The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 117 (50) ◽  
pp. 32145-32154
Author(s):  
Niklas Lonnemann ◽  
Shirin Hosseini ◽  
Carlo Marchetti ◽  
Damaris B. Skouras ◽  
Davide Stefanoni ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Active Form ◽  
Specific Inhibitor ◽  
Morris Water Maze Test ◽  
Model Of Alzheimer’S Disease

Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer’s disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.

scholarly journals Synaptic Plasticity Defect Following Visual Deprivation in Alzheimer's Disease Model Transgenic Mice

2012 ◽  
Vol 32 (23) ◽  
pp. 8004-8011 ◽  
Author(s):  
C. M. William ◽  
M. L. Andermann ◽  
G. J. Goldey ◽  
D. K. Roumis ◽  
R. C. Reid ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Transgenic Mice ◽  
Disease Model ◽  
Visual Deprivation

scholarly journals Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuan-Yuan Xie ◽  
Ting-Ting Pan ◽  
De-en Xu ◽  
Xin Huang ◽  
Yong Tang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Short Term Memory ◽  
Therapeutic Potential ◽  
Disease Model ◽  
Model Mouse ◽  
Oligodendrocyte Precursor ◽  
Myelin Deficits ◽  
M1 Muscarinic

Disrupted myelin and impaired myelin repair have been observed in the brains of patients and various mouse models of Alzheimer’s disease (AD). Clemastine, an H1-antihistamine, shows the capability to induce oligodendrocyte precursor cell (OPC) differentiation and myelin formation under different neuropathological conditions featuring demyelination via the antagonism of M1 muscarinic receptor. In this study, we investigated if aged APPSwe/PS1dE9 mice, a model of AD, can benefit from chronic clemastine treatment. We found the treatment reduced brain amyloid-beta deposition and rescued the short-term memory deficit of the mice. The densities of OPCs, oligodendrocytes, and myelin were enhanced upon the treatment, whereas the levels of degraded MBP were reduced, a marker for degenerated myelin. In addition, we also suggest the role of clemastine in preventing OPCs from entering the state of cellular senescence, which was shown recently as an essential causal factor in AD pathogenesis. Thus, clemastine exhibits therapeutic potential in AD via preventing senescence of OPCs.

scholarly journals Stimulation of the Hippocampal POMC/MC4R Circuit Alleviates Synaptic Plasticity Impairment in an Alzheimer’s Disease Model

Cell Reports ◽  
2016 ◽  
Vol 17 (7) ◽  
pp. 1819-1831 ◽  
Author(s):  
Yang Shen ◽  
Min Tian ◽  
Yuqiong Zheng ◽  
Fei Gong ◽  
Amy K.Y. Fu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Disease Model ◽  
Stimulation Of
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