Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease

Yang, Wei; Zhou, Xueyan; Zimmermann, Helena R.; Cavener, Douglas R.; Klann, Eric; Ma, Tao

doi:10.1016/j.neurobiolaging.2016.02.005

Cited by 74 publications

(70 citation statements)

References 46 publications

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“…) and PERK repression in APP‐PS1 mice alleviates LTD impairment (Yang et al . ). Genetic deletion of PERK in 5xFAD mice lowers ATF4 expression and rescues memory deficits (Devi and Ohno ).…”

Section: Linking Upr Activation To Neurodegenerationmentioning

confidence: 97%

Fine‐tuning PERK signaling for neuroprotection

Halliday

Hughes

Mallucci

2017

Journal of Neurochemistry

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Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress because of protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch, is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the tauopathies. Recently, numerous genetic and pharmacological studies in mice have demonstrated the effectiveness of inhibiting the UPR for eliciting therapeutic benefit and boosting memory. In particular, fine-tuning the level of PERK inhibition to provide neuroprotection without adverse side effects has emerged as a safe, effective approach. This includes the recent discovery of licensed drugs that can now be repurposed in clinical trials for new human treatments for dementia. This review provides an overview of the links between UPR overactivation and neurodegeneration in protein misfolding disorders. It discusses recent therapeutic approaches targeting this pathway, with a focus on treatments that fine-tune PERK signaling.

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Section: Linking Upr Activation To Neurodegenerationmentioning

confidence: 97%

Fine‐tuning PERK signaling for neuroprotection

Halliday

Hughes

Mallucci

2017

Journal of Neurochemistry

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“…Hippocampal slice preparation and electrophysiology. Acute 400-μm transverse hippocampal slices were prepared using a Leica VT1200S vibratome as described (69). Briefly, slices were maintained at room temperature before experimentation (2 hours) in artificial cerebrospinal fluid (ACSF) containing the following: 118 mM NaCl, 3.5 mM KCl, 2.5 mM CaCl 2 , 1.3 mM MgSO 4 , 1.25 mM NaH 2 PO 4 , 5 mM NaH-CO 3 , and 15 mM glucose, bubbled with 95% O 2 /5% CO 2 .…”

Section: Figure 3 Suppression Of Ampkα Does Not Alter Ad-associated mentioning

confidence: 99%

“…SUnSET assay. Acute 400-μm transverse hippocampal slices were prepared using a Leica VT1200S vibratome as described (69). Slices Immunohistochemistry for mouse tissue.…”

Section: Figure 3 Suppression Of Ampkα Does Not Alter Ad-associated mentioning

confidence: 99%

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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“…Aβ increases p-PKR and p-eIF2α in cultured neurons, and a reduction in PKR diminished Aβ-associated toxicity (Chang et al, 2002a). Contextual fear learning and mGluR-dependent long-term depression, both of which are affected upon eIF2α phosphorylation dysregulation, are impaired in AD mouse models, and the reduction of PERK levels rescues these deficits (Costa-Mattioli et al, 2005, 2007; Devi and Ohno, 2014; Trinh et al, 2014; Yang et al, 2016; Zhu et al, 2011). The contribution of GCN2 to eIF2α phosphorylation in AD is less clear.…”

Section: Neurodegenerative Diseases Associated With Dysregulation Of mentioning

confidence: 99%

“…Additional studies in other disease models suggest that drugs that increase eIF2 activity might also be used to treat AD and tauopathy (Halliday et al, 2017; Yang et al, 2016; Zhu et al, 2013). However, while these results are potentially exciting, a careful examination of the role of eIF2α phosphorylation in ALS illustrates the importance of exercising caution in applying new treatments to patients.…”

Section: Neurodegenerative Diseases Associated With Dysregulation Of mentioning

confidence: 99%

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

Kapur

Monaghan

Ackerman

2017

Neuron

180

167

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SUMMARY Dynamic regulation of mRNA translation initiation and elongation is essential for the survival and function of neural cells. Global reductions in translation initiation resulting from mutations in the translational machinery or inappropriate activation of the integrated stress response may contribute to pathogenesis in a subset of neurodegenerative disorders. Aberrant proteins generated by non-canonical translation initiation may be a factor in the neuron death observed in the nucleotide repeat expansion diseases. Dysfunction of central components of the elongation machinery, such as the tRNAs and their associated enzymes, can cause translation infidelity and ribosome stalling, resulting in neurodegeneration. Taken together, dysregulation of mRNA translation is emerging as a unifying mechanism underlying the pathogenesis of many neurodegenerative disorders.

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Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease

Cited by 74 publications

References 46 publications

Fine‐tuning PERK signaling for neuroprotection

Fine‐tuning PERK signaling for neuroprotection

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

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

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