Activation of CaMKIIα regulates hippocampal mitochondrial metabolism and attenuates neuroinflammation: A novel therapeutic target for obesity-associated neurocognitive disorders

Obesity is strongly associated with cognitive impairment, especially in memory. However, the underlying molecular mechanisms remain unclear. Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), a key synaptic kinase, regulates synaptic plasticity and hippocampal memory function through N-methyl-D-aspartate receptor signaling and is also involved in metabolic and inflammatory regulation. However, the precise molecular mechanisms by which hippocampal CaMKIIα mediates obesity-associated mitochondrial dysfunction, neuroinflammation, and cognitive impairment remain unclear. Given the critical role of the hippocampus in cognitive function, this study analyzed obesity-associated changes in molecular pathways in the hippocampal tissue of obese mice. Pathway enrichment analysis of the identified phosphopeptides revealed that the calcium signaling pathway was the most significantly dysregulated pathway, with reduced CaMKIIα phosphorylation emerging as the most prominent alteration. Furthermore, targeted metabolomic analysis revealed that obesity disrupts the mitochondrial tricarboxylic acid cycle and induces neuroinflammation, characterized by microglial activation and upregulation of pro-inflammatory cytokines. Notably, hippocampal overexpression of CaMKIIα in obese mice effectively restored mitochondrial metabolic homeostasis, alleviated microglial activation, and reduced the levels of pro-inflammatory cytokines. Taken together, our findings indicate that enhancing CaMKIIα activity ameliorates obesity-induced mitochondrial dysfunction and neuroinflammation, thereby potentially rescuing cognitive deficits associated with obesity. This work identifies CaMKIIα as a regulator of the crosstalk between mitochondrial metabolism and neuroinflammation in the hippocampus, providing a novel therapeutic target for obesity-related neurocognitive disorders.