Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease
Histamine H<sub>3</sub> receptor (H<sub>3</sub>R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H<sub>3</sub>R is elevated in Alzheimer's disease (AD) patients, whether H<sub>3</sub>R antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved H<sub>3</sub>R 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 Ca<sup>2+</sup> 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.
Authors
- Arthur Konnerth (ORCID: https://orcid.org/0000-0002-9548-2676)
- Hanrun Zheng (ORCID: https://orcid.org/0000-0002-2083-2280)
- Yang Zou (ORCID: https://orcid.org/0000-0003-1052-5014)
- Yun Zhang (ORCID: https://orcid.org/0000-0002-8636-183X)
- Hongbo Jia (ORCID: https://orcid.org/0000-0003-1585-2161)
- Yan‐Jiang Wang (ORCID: https://orcid.org/0000-0002-6227-6112)
- Jiahui Zhu (ORCID: https://orcid.org/0000-0001-9576-5636)
- Linda Yang (ORCID: https://orcid.org/0000-0002-1671-8792)
- Zhiqi Yang (ORCID: https://orcid.org/0000-0002-4139-4371)
- Shiqi Li (ORCID: https://orcid.org/0000-0002-4420-3964)
- Xiang Liao (ORCID: https://orcid.org/0000-0001-6324-5206)
- Jun Fan (ORCID: https://orcid.org/0000-0002-5445-437X)
- Chunqing Zhang
- Kuan Zhang (ORCID: https://orcid.org/0000-0003-0437-5267)
- Xiaowei Chen (ORCID: https://orcid.org/0000-0001-5420-1359)
Institutions
- nLIGHT (United States) (US)
- Allen Institute for Brain Science (US)
- Guangxi University (CN)
- Army Medical University (CN)
- Chongqing University (CN)
- Chinese Academy of Sciences (CN)
- Runze (China) (CN)
- Suzhou Institute of Biomedical Engineering and Technology (CN)
- Munich Cluster for Systems Neurology (DE)
- Fujian Institute of Research on the Structure of Matter (CN)
- Chongqing Medical University (CN)
- Leibniz Institute for Neurobiology (DE)
Publication Details
- Journal
- Translational Psychiatry
- Published
- 2025-04-05
- DOI
- https://doi.org/10.1038/s41398-025-03358-8
- Citations
- 5
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 4.55
Funders
- National Natural Science Foundation of China