Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer's disease model mice independent of brain amyloid β pathology.

Maintenance of memory and synaptic plasticity depends on protein synthesis, and accumulating evidence implicates a role of dysregulated mRNA translation in cognitive impairments associated with Alzheimer's disease (AD). Accumulating evidence demonstrates hyper-phosphorylation of translation factor eukaryotic elongation factor 2 (eEF2) in the hippocampi of human AD patients as well as transgenic AD model mice. Phosphorylation of eEF2 (at the Thr 56 site) by its only known kinase, eEF2K, leads to inhibition of general protein synthesis.

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

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.

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

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).

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

AMPK is a key regulator at the molecular level for maintaining energy metabolism homeostasis. Mammalian AMPK is a heterotrimeric complex, and its catalytic α subunit exists in 2 isoforms: AMPKα1 and AMPKα2. Recent studies suggest a role of AMPKα overactivation in Alzheimer's disease-associated (AD-associated) synaptic failure.

Pharmacokinetics and distribution of 2-hydroxypropyl-β-cyclodextrin following a single intrathecal dose to cats.

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) is an experimental therapy for Niemann-Pick disease type C (NPC) that reduced neuronal cholesterol and ganglioside storage, reduced Purkinje cell death, and increased lifespan in npc1-/- mice and NPC1 cats. In this study, tissue distribution was investigated in normal cats that received a single 120-mg dose of [ C]-HP-β-CD (approximately 200 μCi/cat) via the cerebellomedullary cistern (CBMC) and lumbar cistern. One cat was euthanized at each of various time points up to 24 hours postdose for subsequent processing and quantitative whole-body autoradiographic analysis.

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

Molecular signaling mechanisms underlying Alzheimer's disease (AD) remain unclear. Maintenance of memory and synaptic plasticity depend on de novo protein synthesis, dysregulation of which is implicated in AD. Recent studies showed AD-associated hyperphosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2), which results in inhibition of protein synthesis.

Genetic removal of eIF2α kinase PERK in mice enables hippocampal L-LTP independent of mTORC1 activity.

Characterization of the molecular signaling pathways underlying protein synthesis-dependent forms of synaptic plasticity, such as late long-term potentiation (L-LTP), can provide insights not only into memory expression/maintenance under physiological conditions but also potential mechanisms associated with the pathogenesis of memory disorders. Here, we report in mice that L-LTP failure induced by the mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) inhibitor rapamycin is reversed by brain-specific genetic deletion of PKR-like ER kinase, PERK (PERK KO), a kinase for eukaryotic initiation factor 2α (eIF2α). In contrast, genetic removal of general control non-derepressible-2, GCN2 (GCN2 KO), another eIF2α kinase, or treatment of hippocampal slices with the PERK inhibitor GSK2606414, does not rescue rapamycin-induced L-LTP failure, suggesting mechanisms independent of eIF2α phosphorylation.