| First Author | Zimmermann HR | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 7 | Pages | 3511-3527 |
| PubMed ID | 32213711 | Mgi Jnum | J:312217 |
| Mgi Id | MGI:6751756 | Doi | 10.1172/JCI133982 |
| Citation | Zimmermann HR, et al. (2020) Brain-specific repression of AMPKalpha1 alleviates pathophysiology in Alzheimer's model mice. J Clin Invest 130(7):3511-3527 |
| abstractText | AMPK is a key regulator at the molecular level for maintaining energy metabolism homeostasis. Mammalian AMPK is a heterotrimeric complex, and its catalytic alpha subunit exists in 2 isoforms: AMPKalpha1 and AMPKalpha2. Recent studies suggest a role of AMPKalpha overactivation in Alzheimer's disease-associated (AD-associated) synaptic failure. However, whether AD-associated dementia can be improved by targeting AMPK remains unclear, and roles of AMPKalpha isoforms in AD pathophysiology are not understood. Here, we showed distinct disruption of hippocampal AMPKalpha isoform expression patterns in postmortem human AD patients and AD model mice. We further investigated the effects of brain- and isoform-specific AMPKalpha repression on AD pathophysiology. We found that repression of AMPKalpha1 alleviated cognitive deficits and synaptic failure displayed in 2 separate lines of AD model mice. In contrast, AMPKalpha2 suppression did not alter AD pathophysiology. Using unbiased mass spectrometry-based proteomics analysis, we identified distinct patterns of protein expression associated with specific AMPKalpha isoform suppression in AD model mice. Further, AD-associated hyperphosphorylation of eukaryotic elongation factor 2 (eEF2) was blunted with selective AMPKalpha1 inhibition. Our findings reveal isoform-specific roles of AMPKalpha in AD pathophysiology, thus providing insights into potential therapeutic strategies for AD and related dementia syndromes. |
