Ultramicronized palmitoylethanolamide restores astrocyte-neuron metabolic coupling and Klotho/FGF21 signaling in a triple-transgenic mouse model of Alzheimer’s disease

Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, is characterized by metabolic deficiency, neuroinflammation, and synaptic impairment. Astrocyte-neuron metabolic coupling regulates cerebral energy homeostasis through key metabolites such as lactate, glutamate, and taurine. We investigated the therapeutic potential of ultramicronized-palmitoylethanolamide (um-PEA) in restoring the homeostasis of these metabolites in the triple transgenic (3 ×Tg-AD) mouse model of AD. Using in vivo magnetic resonance imaging and spectroscopy (MRI/MRS) combined with Western blot, we evaluated the effects of chronic um-PEA treatment on lactate-glutamate dynamics and taurine metabolism in the frontal cortex and hippocampus of 6- and 12 month-old mice. Our findings demonstrate that 3 ×Tg-AD mice exhibit lactate accumulation, glutamine/glutamate imbalance, and taurine depletion, alongside reduced expression of metabolic processes regulators such as FGF21, Klotho, and insulin receptor. Treatment with um-PEA successfully restored these metabolic changes by: (i) rebalancing lactate-glutamate metabolism, (ii) increasing taurine synthesis and transport, (iii) upregulating FGF21, Klotho, and insulin receptor expression, and (iv) modulating the metalloproteases ADAM10 and ADAM17, which regulate Klotho processing. These results identify um-PEA as a promising metabolic modulator capable of mitigating AD-related neurodegenerative processes. By targeting astrocyte-neuron metabolism and enhancing both FGF21 and Klotho pathways, um-PEA holds significant potential as an adjunctive therapeutic strategy for AD.