Isoform-specific roles and overlooked complexity of AMPKα in Alzheimer's disease

During Alzheimer's disease (AD) progression, neurons lose their regulation of signaling pathways, energy homeostasis, and accumulate pathogenic amyloid and tau proteins—all of which are detrimental for maintaining brain health and function. A better understanding of the molecular mechanisms underpinning these processes could provide insights into the pathogenesis of AD and related dementias (ADRDs). AMP-activated protein kinase (AMPK) is the central cellular energy nexus, integrating the anabolic and catabolic processes of the cell in response to energetic demands. AMPK also plays a role in pathogenic protein accumulation. Notably, AMPK is upstream of multiple signaling pathways controlling de novo protein synthesis/mRNA translation, which is essential for maintenance of long-term synaptic plasticity and memory. AMPK is a heterotrimeric protein with a catalytic α subunit and regulatory β/γ subunits. The α subunit of AMPK exists in two isoforms: α1 and α2, and their roles in AD are unclear. Recent studies have shown a specific role of the AMPKα isoforms in regulating synaptic plasticity and modulating AD pathophysiology. AMPKα isoform dysregulation has also been found in postmortem tissue from human patients with AD and animal models, and recent studies implicate isoform-specific roles of AMPKα during the development of AD pathophysiology. Here we focus on discussion of the new findings on the roles of AMPKα isoforms in the broader context of AD etiology and targeting the isoforms as potential novel therapeutic strategy for ADRDs.