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.

Decreased Levels of Blood AMPKα1 but not AMPKα2 Isoform in Patients with Mild Cognitive Impairment and Alzheimer's Disease: A Pilot Study.

Background: There is an urgent need to develop feasible biomarkers for diagnosis and prognosis of Alzheimer's disease (AD). Mounting evidence implicates that dysregulation of energy metabolism is a key and early event in AD pathogenesis. AMP-activated protein kinase (AMPK) is a central molecular sensor that plays a critical role in maintaining cellular energy homeostasis, and aberrant brain AMPK activities are linked to AD pathophysiology.

Brain-specific suppression of AMPKα2 isoform impairs cognition and hippocampal LTP by PERK-mediated eIF2α phosphorylation.

The AMP-activated protein kinase (AMPK) is a molecular sensor to maintain energy homeostasis. The two isoforms of the AMPK catalytic subunit (AMPKα1 and α2) are both expressed in brains, but their roles in cognition are unknown. We generated conditional knockout mice in which brain AMPKα isoforms are selectively suppressed (AMPKα1/α2 cKO), and determined the isoform-specific effects in mice of either sex on cognition and synaptic plasticity.

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.

Therapeutic Potential of AMP-Activated Protein Kinase in Alzheimer's Disease.

Currently there is no cure or effective disease-modifying therapy for Alzheimer's disease (AD), the most common form of dementia that is becoming a global threat to public health. It is important to develop novel therapeutic strategies targeting AD pathophysiology particularly synaptic failure and cognitive impairments. Recent studies revealed several molecular signaling pathways potentially linked to brain pathology and synaptic failure in AD, including AMP-activated protein kinase (AMPK), a master kinase that plays a central role in the maintenance of cellular energy homeostasis.

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.

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

Mounting evidence indicates that impairments of synaptic efficacy and/or plasticity may be a key step in the development of Alzheimer's disease (AD) pathophysiology. Among the 2 major forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), much less is known about how LTD is regulated in AD and its molecular mechanisms. Recent studies indicate that metabotropic glutamate receptor 5 (mGluR5) may function as a receptor and/or co-receptor for amyloid beta.