M1 PAMs for Age-Related Cognitive Impairments

M1 PAM 用于治疗与年龄相关的认知障碍

• 批准号: 9919471
• 负责人: Carrie Kimberly Jones
• 金额: $ 66.67万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919471
• 关键词: 20 year old; Acetylcholine; Acetylcholinesterase Inhibitors; Address; Adverse effects; Age-associated memory impairment; Aging; Agonist; Allosteric Site; Alzheimer' s Disease; Alzheimer' s disease patient; Aricept; Arousal; Attention; Behavioral; Binding Sites; Chemosensitization; Clinical Trials; Cognition; Cognitive; Dementia; Development; Dose; Dose-Limiting; Electroencephalography; Evaluation; Female; Future; Glutamate Receptor; Glutamates; Hippocampus (Brain); Impaired cognition; Impairment; Measures; Mediating; Memory; Microdialysis; Modeling; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Acetylcholine Receptor M3; N-Methylaspartate; Neurosciences; Peripheral; Physiological; Play; Population; Process; Prosencephalon; Regulation; Risk Factors; Role; Series; Short-Term Memory; Signal Transduction; Site; Sleep; Sleep Architecture; Sleep Disorders; Sleep disturbances; Specificity; Techniques; Testing; Therapeutic; Time; United States; acetylcholine receptor agonist; age related; aged; analog; cholinergic; classical conditioning; cognitive function; cognitive performance; donepezil; drug discovery; efficacy study; extracellular; glutamatergic signaling; human old age (65+); in vivo; male; neurotransmission; nonhuman primate; normal aging; novel; novel strategies; novel therapeutics; positive allosteric modulator; potential biomarker; pre-clinical; receptor; response; restoration; sex; side effect; tool; translational study; transmission process

PROJECT SUMMARY It is estimated that in the United States alone there will be nearly 70 million people over the age of 65 by the year 2030. Yet, there remains a critical unmet need to understand and identify novel therapeutic strategies to address age-related impairments in arousal, cognitive function, and sleep architecture. Agents such as acetylcholinesterase inhibitors (AChEIs) that enhance overall cholinergic transmission or activate muscarinic acetylcholine receptors (mAChRs) have been developed to ameliorate the loss of cognitive function in normal aging and Alzheimer’s disease (AD) populations. Accumulating evidence indicates that enhancement of central cholinergic neurotransmission through activation of the M1 mAChR subtype represents an exciting alternative approach for the treatment of impairments in cognition, arousal and sleep observed in normal aging and AD. M1 is co-localized with the NR1a subunit of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR). Selective activation of M1 potentiates prefrontal cortical (PFC) and hippocampal NMDAR currents and enhances both PFC- and hippocampal-mediated associative learning and memory functions. Recently we successfully optimized a novel series of isoindolinone M1 positive allosteric modulators (PAMs), represented by VU0453595, as an alternative strategy for the selective activation of M1. The discovery and characterization of VU0453595 represents an unprecedented opportunity to characterize the impact of selective M1 potentiation on cortical ACh neurotransmission and cognition, arousal and sleep dysfunction associated with normal aging in preclinical species. In Aim 1, we will determine effects of VU0453595 alone and in combination with the AChEI donepezil on cortical acetylcholine and glutamate neurotransmission using in vivo microdialysis techniques in young and aged male and female mice. Next, we will examine effects of VU0453595 alone and in combination with donepezil to ameliorate age-related impairments in cognition and sleep architecture in aged male and female mice (Aim 2). Finally, in Aim 3 we will investigate whether selective activation of M1 by VU0453595 ameliorates age-related impairments in cognition and sleep architecture in male and female aged NHPs. Together, these translational studies across species will extend our understanding of age-related cognitive dysfunction, a critical risk factor for later onset dementia and AD, and the potential role of M1 modulation for restoration of age-related impairments in cognition and sleep architecture.

项目摘要 据估计，仅在美国，这三人是65岁以上的7000万人 Y2030。然而，仍然是了解和确定新颖的novy治疗策略的至关重要的需求 解决与年龄相关的障碍，认知功能和睡眠结构 乙酰胆碱酯酶抑制剂（ACHEI），可增强总体胆碱能传播或激活毒蕈碱 已经开发出乙酰胆碱受体（MACHR）是为了划定正常认知功能的丧失 衰老和阿尔茨海默氏病（AD）流行。 M1 MACHR子类型的胆碱能神经传递 在正常衰老和地址中观察到的认知，唤醒和睡眠障碍的方法。 M1与谷氨酸受体（NMDAR）的N-甲基-D-天冬氨酸亚型的NR1A亚基共定位。 M1的选择性激活前额叶皮质（PFC）和海马NMDAR电流以及 增强了PFC和海马介导的相关哮喘病。 成功优化了一系列新型岛屿M1阳性变构调节剂（PAM），被压抑 VU0453595，作为M1选择性激活的替代策略。 VU0453595压制一个未经预先的机会来表征选择性M1潜力的影响 关于皮质ACH神经传递和认知，正常衰老的唤醒和睡眠功能障碍 在AIM 1中，我们将单独确定VU0453595的影响 在皮质乙酰胆碱和谷氨酸神经传递上，使用体内微透析 接下来，我们将使用VU0453595的效果 结合多奈替齐（Donepezil 老年男性和雌性小鼠（AIM 2）。 VU0453595改善了男性和女性老年人认知和缝隙中与年龄相关的障碍 NHP一起，这些跨物种的翻译研究将扩展我们对年龄相关的 认知功能障碍，以后发作痴呆和AD的关键危险因素以及M1的潜在作用 调节认知和Sleechitector中与年龄相关的障碍的修复。