Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer’s disease model mice

Beckelman, Brenna C.; Yang, Wei; Kasica, Nicole P.; Zimmermann, Helena R.; Zhou, Xueyan; Keene, C. Dirk; Ryazanov, Alexey G.; Ma, Tao

doi:10.1172/jci122954

Cited by 75 publications

(105 citation statements)

References 64 publications

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“…We used the rapid Golgi-Cox staining technique to assess spine density and morphology changes of dendritic spines within area CA1 of the hippocampus. Consistent with a previous study (28), overall dendritic spine density in Tg mice was significantly decreased as compared with that in WT controls ( Figure 4B). Importantly, AD-associated reduction of dendritic spine density was restored by suppressing AMPKα1, but not AMPKα2 ( Figure 4B).…”

Section: Resultssupporting

confidence: 92%

“…Additionally, we examined hippo campal protein levels of the structural components of protein phosphatase 2A (PP2A), a potential phosphatase and key regulator for AMPK activity (39,40), and did not observe any alterations (Supplemental Figure 4, C-E). Levels of eEF2 phosphorylation were elevated in hippocampi of Tg mice, in agreement with recent studies (28,41). Markedly, AD-associated eEF2 hyperphosphorylation was restored with selective AMPKα1, but not AMPKα2, suppression ( Figure 5A).…”

Section: Resultssupporting

confidence: 91%

“…Indeed, cognitive impairments associated with multiple neurodegenerative diseases are linked to defects in capacity of de novo protein synthesis (23)(24)(25). Consistently, a recent study shows that repression of eEF2K and thus eEF2 phosphorylation is sufficient to improve multiple aspects of pathophysiology in AD model mice (28).…”

Section: Discussionmentioning

confidence: 72%

“…To investigate regulation of AMPKα isoforms in AD, we first examined post- any differences among all genotypes ( Figure 2C and Supplemental Figure 1, F and G). We then tested the mice in the novel object recognition (NOR) task to evaluate their long-term hippocampusdependent recognition memory (28). WT and α1/cre mice exhibited normal cognition, as indicated by their preference for the novel object over the familiar object on the test day (i.e., significantly more interaction with the novel object) ( Figure 2D).…”

Section: Resultsmentioning

confidence: 99%

“…Repression of brain AMPKα1 restores abnormal eEF2 phosphorylation and de novo protein synthesis deficits in Tg19959 mice. De novo protein synthesis is essential for memory formation and synaptic plasticity and is notably impaired in AD (23,28,38).…”

Section: Resultsmentioning

confidence: 99%

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Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Zimmermann¹,

Yang²,

Kasica³

et al. 2020

Journal of Clinical Investigation

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Figure 1. Expression of AMPKα isoforms is dysregulated in AD hippocampus. (A) Hippocampus (Hip) lysate from sAD patients showed increased AMPKα1 and decreased AMPKα2 levels as compared with those of age-matched controls (CT). n = 10 with up to 4 technical replicates. *P = 0.0119; **P = 0.0014, unpaired t test. (B) Representative images of AMPKα isoform dysregulation in area CA1 of hippocampus in AD and age-matched control patients. Scale bar: 50 μm. Immunohistochemical experiments were replicated independently 3 times. (C) AMPKα isoform expression was unaffected in cerebellum (CER) samples from AD patients. n = 5 with up to 3 technical replicates. P = 0.8457 for AMPKα1; P = 0.9870 for AMPKα2, unpaired t test. (D) Hippocampal lysate from LBD patients had unaffected AMPKα isoform levels. n = 4 for control; n = 3 for LBD with 1 technical replicate. P = 0.9146 for AMPKα1; P = 0.5635 for AMPKα2, unpaired t test. (E) Levels of AMPK isoforms were unaltered in hippocampal tissue from FTD patients. n = 8 for control with 1 technical replicate; n = 5 for FTD with up to 3 technical replicates. P = 0.9283 for AMPKα1; P = 0.335 for AMPKα2, unpaired t test. (F) AMPKα1 levels were significantly increased in cortical lysates from FAD patients, while AMPKα2 levels were unaffected. n = 5 with 4 technical replicates. **P = 0.0060 for AMPKα1; P = 0.9412 for AMPKα2, unpaired t test. (G) AMPKα1 levels were significantly increased in hippocampal lysates from Tg19959 AD model mice compared with WT controls. AMPKα2 levels were unaffected. n = 7 with up to 2 technical replicates. **P = 0.0023 for AMPKα1; P = 0.9094 for AMPKα2, unpaired t test. Box-and-whisker plots represent the interquartile range, with the line across the box indicating the median. Whiskers show the highest and lowest values detected. (H) Immunofluorescent labeling of DAPI (blue) and AMPKα1 (red) distribution in area CA1 mouse hippocampal slices. n = 3. Scale bar: 200 μm.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Zimmermann¹,

Yang²,

Kasica³

et al. 2020

Journal of Clinical Investigation

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Detection of early proteomic alterations in 5xFAD Alzheimer's disease neonatal mouse model via MALDI‐MSI

Uras

Karayel-Basar

Sahin

et al. 2023

Alzheimer's & Dementia

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Alzheimer's disease (AD) is a debilitating neurodegenerative disorder, characterized by memory deficit and dementia. AD is considered a multifactorial disorder where multiple processes like amyloid‐beta and tau accumulation, axonal degeneration, synaptic plasticity, and autophagic processes plays an important role. In this study, the spatial proteomic differences in the neonatal 5xFAD brain tissue were investigated using MALDI‐MSI coupled to LC‐MS/MS, and the statistically significantly altered proteins were associated with AD. Thirty‐five differentially expressed proteins (DEPs) between the brain tissues of neonatal 5xFAD and their littermate mice were detected via MALDI‐MSI technique. Among the 35 proteins identified, 26 of them were directly associated with AD. Our results indicated a remarkable resemblance in the protein expression profiles of neonatal 5xFAD brain when compared to AD patient specimens or AD mouse models. These findings showed that the molecular alterations in the AD brain existed even at birth and that some proteins are neurodegenerative presages in neonatal AD brain.Highlights Spatial proteomic alterations in the 5xFAD mouse brain compared to the littermate. 26 out of 35 differentially expressed proteins associated with Alzheimer's disease (AD). Molecular alterations and neurodegenerative presages in neonatal AD brain. Alterations in the synaptic function an early and common neurobiological thread.

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Suppression of eEF2 phosphorylation alleviates synaptic failure and cognitive deficits in mouse models of Down syndrome

Wang,

Yang,

Zhou

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONCognitive impairment is a core feature of Down syndrome (DS), and the underlying neurobiological mechanisms remain unclear. Translation dysregulation is linked to multiple neurological disorders characterized by cognitive impairments. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis.METHODSWe used genetic and pharmacological methods to suppress eEF2K in two lines of DS mouse models. We further applied multiple approaches to evaluate the effects of eEF2K inhibition on DS pathophysiology.RESULTSWe found that eEF2K signaling was overactive in the brain of patients with DS and DS mouse models. Inhibition of eEF2 phosphorylation through suppression of eEF2K in DS model mice improved multiple aspects of DS‐associated pathophysiology including de novo protein synthesis deficiency, synaptic morphological defects, long‐term synaptic plasticity failure, and cognitive impairments.DISCUSSIONOur data suggested that eEF2K signaling dysregulation mediates DS‐associated synaptic and cognitive impairments.Highlights Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) is increased in the Down syndrome (DS) brain. Suppression of the eEF2 kinase (eEF2K) alleviates cognitive deficits in DS models. Suppression of eEF2K improves synaptic dysregulation in DS models. Cognitive and synaptic impairments in DS models are rescued by eEF2K inhibitors.

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Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer’s disease model mice

Cited by 75 publications

References 64 publications

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Detection of early proteomic alterations in 5xFAD Alzheimer's disease neonatal mouse model via MALDI‐MSI

Suppression of eEF2 phosphorylation alleviates synaptic failure and cognitive deficits in mouse models of Down syndrome

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