Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease

Histamine H₃ receptor (H₃R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H₃R is elevated in Alzheimer’s disease (AD) patients, whether H₃R antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved H₃R antagonist/inverse agonist that treats narcolepsy. Here, we find that pitolisant reverses AD-like pathophysiology and cognitive impairments in an AD mouse model. Behavioral assays and in vivo wide-field Ca²⁺ imaging revealed that recognition memory, learning flexibility, and slow-wave impairment were all improved following the 15-day pitolisant treatment. Improved recognition memory was tightly correlated with slow-wave coherence, suggesting slow waves serve as a biomarker for treatment response and for AD drug screening. Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments.