Chen Briana K, Hunsberger Holly C, Whye Alicia, Matthews Louise C, Yook Alyson, Willner Moshe J, Logan Ryan W, Johns Stefanie, Weisblum Eric, Denny Christine A
Doctoral Program in Neurobiology and Behavior (NB&B), Columbia University, New York, NY, 10027, USA.
Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), NYSPI Kolb Research Annex, 1051 Riverside Drive, Unit 87, New York, NY, 10032, USA.
Alzheimers Res Ther. 2025 Jul 15;17(1):160. doi: 10.1186/s13195-025-01804-9.
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-HTR) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood.
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-HTR 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.
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.
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.
阿尔茨海默病（AD）是痴呆症的主要病因。获批的用于延缓认知衰退或减轻神经精神症状的药物有限。众多针对AD的单药临床试验均未达到治疗终点，这很可能是由于AD的复杂性所致。多模式治疗干预更有可能通过针对AD中涉及的多个靶点来改善症状。在此，我们研究了同时靶向N-甲基-D-天冬氨酸受体（NMDARs）和5-羟色胺4型受体（5-HTR）是否可能对AD小鼠模型产生有益影响，因为此前已分别证明它们可改善认知和/或情绪。
对雄性和雌性对照（Ctrl）小鼠或APP/PS1小鼠进行单次、间歇性或长期给药，药物包括：1）生理盐水；2）（R,S）-氯胺酮，一种NMDAR拮抗剂；3）普芦卡必利，一种5-HTR激动剂；或4）（R,S）-氯胺酮 + 普芦卡必利，以同时针对共病的神经精神和认知缺陷。随后进行行为学检测以测量认知、持续性行为、食欲减退和/或睡眠。对大脑进行胶质纤维酸性蛋白（GFAP）免疫组织化学处理。
在APP/PS1小鼠的情境恐惧条件反射（CFC）范式中，单次和长期给予（R,S）-氯胺酮 + 普芦卡必利可通过增强记忆恢复来改善认知衰退。药物疗效在雌性小鼠中比在雄性小鼠中效果差，且具有年龄依赖性。长期给予（R,S）-氯胺酮 + 普芦卡必利可降低雌性小鼠海马体中的GFAP免疫反应性。
我们的结果表明，联合给予（R,S）-氯胺酮 + 普芦卡必利是一种治疗AD认知衰退的新型多模式治疗策略。未来的工作将进一步明确这些相互作用，以推动临床开发。
