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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.

The ubiquitin-proteasome pathway (UPP) of protein degradation has many roles in synaptic plasticity that underlies memory. Work on both invertebrate and vertebrate model systems has shown that the UPP regulates numerous substrates critical for synaptic plasticity. Initial research took a global view of ubiquitin-protein degradation in neurons. Subsequently, the idea of local protein degradation was proposed a decade ago. In this review, we focus on the functions of the UPP in long-term synaptic plasticity and discuss the accumulated evidence in support of the idea that the components of the UPP often have disparate local roles in different neuronal compartments rather than a single cell-wide function.

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. Moreover, we demonstrate that phosphorylation of eukaryotic elongation factor 2 (eEF2) is significantly decreased in PERK KO mice but unaltered in GCN2 KO mice or slices treated with the PERK inhibitor. Reduction in eEF2 phosphorylation results in increased general protein synthesis, and thus could contribute to the mTORC1-independent L-LTP in PERK KO mice. We further performed experiments on mutant mice with genetic removal of eEF2K (eEF2K KO), the only known kinase for eEF2, and found that L-LTP in eEF2K KO mice is insensitive to rapamycin. These data, for the first time, connect reduction in PERK activity with the regulation of translation elongation in enabling L-LTP independent of mTORC1. Thus, our findings indicate previously unrecognized levels of complexity in the regulation of protein synthesis-dependent synaptic plasticity. Read the Editorial Highlight for this article on page 119. Cover Image for this issue: doi: 10.1111/jnc.14185.

Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer’s disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets.