AMPK Activator MK ‐8722 Improves Spatial Memory Deficit and Alters Metabolome in APP / PS1 AD Mouse Model

ABSTRACT Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP‐activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan‐AMPK activator MK‐8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6–8 months. MK‐8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK‐8722 selectively improved AD‐associated hippocampal‐dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK‐8722 did not alter hippocampal long‐term potentiation (LTP). In‐depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine‐dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK‐8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience. image