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 alpha subunit exists in 2 isoforms: AMPK alpha 1 and AMPK alpha 2. Recent studies suggest a role of AMPK alpha 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 AMPK alpha. isoforms in AD pathophysiology are not understood. Here, we showed distinct disruption of hippocampal AMPK alpha. isoform expression patterns in postmortem human AD patients and AD model mice. We further investigated the effects of brain- and isoform-specific AMPK alpha repression on AD pathophysiology. We found that repression of AMPK alpha 1 alleviated cognitive deficits and synaptic failure displayed in 2 separate lines of AD model mice. In contrast, AMPK alpha 2 suppression did not alter AD pathophysiology. Using unbiased mass spectrometry-based proteomics analysis, we identified distinct patterns of protein expression associated with specific AMPK alpha isoform suppression in AD model mice. Further, AD-associated hyperphosphorylation of eukaryotic elongation factor 2 (eEF2) was blunted with selective AMPK alpha 1 inhibition. Our findings reveal isoform-specific roles of AMPK alpha in AD pathophysiology, thus providing insights into potential therapeutic strategies for AD and related dementia syndromes.