Combinatorial targeting of NMDARs and 5-HT4Rs exerts beneficial effects in a mouse model of Alzheimer's disease.
| Publication Type | Academic Article |
| Authors | Chen B, Hunsberger H, Whye A, Matthews L, Yook A, Willner M, Logan R, Johns S, Weisblum E, Denny C |
| Journal | Alzheimers Res Ther |
| Volume | 17 |
| Issue | 1 |
| Pagination | 160 |
| Date Published | 07/15/2025 |
| ISSN | 1758-9193 |
| Keywords | Alzheimer Disease, Receptors, Serotonin, 5-HT4, Receptors, N-Methyl-D-Aspartate, Serotonin 5-HT4 Receptor Agonists, Benzofurans, Excitatory Amino Acid Antagonists |
| Abstract | BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT4R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood. METHODS: Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (R,S)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT4R agonist; or 4) (R,S)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry. RESULTS: Single and chronic administration of (R,S)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (R,S)-ketamine + prucalopride treatment in females. CONCLUSIONS: Our results indicate that combined administration of (R,S)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development. |
| DOI | 10.1186/s13195-025-01804-9 |
| PubMed ID | 40665449 |
| PubMed Central ID | PMC12261665 |