Sustained Palmitoylethanolamide Infusion Restores Incentive Motivation and Synaptic Plasticity in the Tg2576 Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is increasingly recognized as a disorder not only of cognition but also of motivation and emotional regulation. Apathy and anhedonia often precede memory deficits, implicating early dysfunction in reward-related circuits. This study investigated whether chronic infusion of palmitoylethanolamide (PEA), a lipid-derived PPARα agonist, could restore motivational behavior and dendritic plasticity in the Tg2576 mouse model of AD. The motivational behavior of mice that received sustained-release PEA pellets for 6 months was assessed by using the conditioned place preference (CPP) paradigm. Morphological and molecular analyses were conducted in the entorhinal cortex (EC), dentate gyrus (DG), and prefrontal cortex (PFC). In Tg2576 mice, PEA significantly rescued CPP performance, increased basal dendritic spines in WT mice in the EC, and both basal and apical dendritic expression in EC and DG from Tg2576 mice, and upregulated the expression of both PPAR-α and brain-derived neurotrophic factor (BDNF) in the PFC. Interestingly, the BDNF increase occurred even in the absence of baseline deficits, suggesting a trophic-enhancement effect. These findings suggest that the PEA-PPARα-BDNF axis may be a potential mechanism for restoring motivation and synaptic integrity in an AD-like mouse model. Lipid-based neuromodulation may therefore offer novel therapeutic routes for addressing non-cognitive symptoms and affective circuitopathy in neurodegenerative diseases.