Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer's model mice.

AMP-activated protein kinase (AMPK) is a key regulator at the molecular level to maintain energy metabolism homeostasis. Mammalian AMPK is a heterotrimeric complex and its catalytic alpha subunit exists in two isoforms: AMPKalpha1 and AMPKalpha2. Recent studies suggest a role of AMPKalpha over-activation in 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 post mortem 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 two 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 hyper-phosphorylation 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 strategy for AD and related dementia syndromes.