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

Abstract

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. AMPKα2 cKO but not AMPKα1 cKO displayed impaired cognition and hippocampal late long-term potentiation (L-LTP). Further, AMPKα2 cKO mice exhibited decreased dendritic spine density and abnormal spine morphology in hippocampus. Electron microscope imaging demonstrated reduced postsynaptic density formation and fewer dendritic polyribosomes in hippocampi of AMPKα2 cKO mice. Biochemical studies revealed unexpected findings that repression of AMPKα2 resulted in increased phosphorylation of mRNA translational factor eIF2α and its kinase PERK. Importantly, L-LTP failure and cognitive impairments displayed in AMPKα2 cKO mice were alleviated by suppressing PERK activity pharmacologically or genetically. In summary, we demonstrate here that brain-specific suppression of AMPKα2 isoform impairs cognition and hippocampal LTP by PERK-mediated eIF2α phosphorylation, providing molecular mechanisms linking metabolism, protein synthesis, and cognition.

Protein expression alteration in hippocampus upon genetic repression of AMPKα isoforms

“…Second, similar to the results from hippocampus, most altered proteins in PFC are uniquely regulated by suppression of either AMPKα1 or α2 (but not both). The results are consistent with recent studies indicating isoform-specific roles of AMPKα in neuronal plasticity, cognitive function, and neurodegenerative diseases(Yang et al, 2020;Zimmermann et al, 2020). As discussed above, AMPK plays a central role in regulating cellular energy homeostasis, disruption of which is indicated many…”

“…AMPKα1 cKO or AMPKα2 cKO ( Figure 1a). We previously demonstrated in these mutant mice that expression of the two AMPKα isoforms are selectively reduced that is, significantly reduced in hippocampus and prefrontal cortex, but unaltered in cerebellum or peripheral organs (e.g., liver, heart) (Yang et al, 2020). Importantly, we did not observe compensated alterations in protein expression levels of the other isoform in the mutant mice ( Figure 1b).…”

“…Recently emerging evidence reveals potential roles of AMPKα isoforms in brain physiology and pathophysiology (Wang, Zimmermann, & Ma, 2019). For instance, suppression of AMPKα2 but not AMPKα1 isoform in mice results in cognitive impairment and synaptic failure (Yang, Zhou, Zimmermann, & Ma, 2020). Moreover, expression of AMPKα isoforms is dysregulated in brains of AD patients and AD animal models, and genetic restoration of brain AMPKα1 level alleviates multiple aspects of pathophysiology in AD model mice (Zimmermann et al, 2020).…”

“…In the current study, we take advantage of two lines of transgenic mice that we recently developed in which the genes for the two AMPKα isoforms are conditionally knocked out in forebrain areas (Yang et al, 2020). Using unbiased mass spectrometry‐based proteomics approach, the study is aimed to identify proteins whose expression pattern is sensitive to suppression of AMPKα isoforms in the brain.…”

“…Additionally, AMPK inhibits (directly or indirectly) the mTORC1 signaling pathway, activation of which promotes synthesis of translational apparatus and cap-dependent translation initiation (Steinberg & Kemp, 2009). A most recent study also indicates a link between AMPKα2 and protein synthesis through mRNA translational initiation factor eIF2 and its kinase PERK (Yang et al, 2020). However, how AMPK isoform modulation influences translation of specific proteins in the brain is unknown.…”