Effects of cannabis on age-related cognitive decline and Alzheimers disease pathology

大麻对与年龄相关的认知能力下降和阿尔茨海默病病理学的影响

• 批准号: 10633300
• 负责人: JENNIFER Lynn BIZON
• 金额: $ 67.68万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633300
• 关键词: Acute; Address; Affect; Age; Age-associated memory impairment; Aging; Agitation; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; Anorexia; Anxiety; Attenuated; Behavioral; Behavioral Symptoms; Biochemical; Brain; Cannabinoids; Cannabis; Chronic; Cognition; Cognitive deficits; Cognitive remediation; Consumption; Data; Elderly; Electrophysiology (science); Exposure to; Functional disorder; Goals; Hippocampus; Human; Impaired cognition; Impairment; Individual; Inflammation; Knowledge; Link; Medial; Mediating; Memory; Modeling; Mus; Nerve Degeneration; Neurobiology; Oral; Pain; Pathology; Performance; Persons; Prefrontal Cortex; Rattus; Recreation; Research; Risk; Route; Shapes; Short-Term Memory; Signal Transduction; Sleeplessness; Smoking; Structure; Synapses; Temporal Lobe; Testing; Tetrahydrocannabinol; adverse outcome; age group; age related; age related neurodegeneration; aged; cannabis administration; executive function; experimental study; inflammatory marker; male; marijuana smoke; marijuana use; marijuana user; middle age; neural; neuroinflammation; neuropathology; novel; pre-clinical research; programs; remediation; sex; spatial memory; tau Proteins; tau aggregation; tau expression; young adult

PROJECT SUMMARY: Older adults are the fastest-growing group of cannabis users in the US. Older adults use cannabis for a variety of reasons, including pain, insomnia, anxiety, and for recreation. Cannabis can, however, also exert robust effects on cognition. Almost all research on cannabis/cannabinoids and cognition has been conducted in young adults, and largely shows that acute administration impairs mnemonic and executive functions mediated by the medial temporal lobe and prefrontal cortex (which are also those most vulnerable to decline in aging and age- related neurodegenerative disease). In contrast, a few studies suggest that cannabinoids can exert distinct effects on the aged compared to the young brain, and preliminary data from our labs show that cannabis can actually enhance cognition selectively in aged rats. Indeed, cannabinoids have been proposed as potential treatments for the age-related neurodegenerative condition Alzheimer's disease (AD), and some preclinical research shows that cannabinoids can attenuate markers linked to AD pathology (e.g., neuroinflammation). Aging studies evaluating cannabis to date, however, are very limited and have not employed either cannabis itself or routes of administration that model those used most frequently by people (smoking and oral consumption). As such, it is unclear how cannabis, as it is actually used, affects cognitive decline and the synaptic dysfunction and AD-like pathology that contribute to cognitive impairments in older subjects. The long-term goal of our program is to determine how cannabis affects cognitive decline in aging and AD, and to determine the mechanisms of such effects. The objective of the current proposal is to model the two most common routes of human cannabis use (smoking and oral consumption) in well-characterized rat models of age-related cognitive decline, and to use these models to begin to elucidate effects of cannabis on behavioral and neurobiological dysfunction associated with aging and AD. Our overarching hypothesis is that cannabis can benefit cognition in aging by attenuating age-associated synaptic dysfunction, neuroinflammation, and tau pathology. Aim 1 will determine how acute cannabis affects performance in young adult and aged rats, as well as the synaptic mechanisms supporting effects of cannabis on cognition in aged subjects. Aim 2 will assess effects of chronic cannabis on cognition in young adult and aged rats, as well as on excitatory/inhibitory signaling and inflammatory markers linked to age-related cognitive impairments. Aim 3 will assess effects of chronic cannabis on AD-like tau pathology and cognition using a novel, targeted AAV-based approach in aged rats. The proposed experiments will be significant because they will provide foundational data concerning whether and how cannabis administration relevant for human consumption yields benefits for age-related cognitive decline and neuropathology.

项目摘要： 老年人是美国增长最快的大麻使用者。老年人将大麻用于各种 包括疼痛，失眠，焦虑和休闲的原因。但是，大麻也可以发挥强大的作用 对认知的影响。几乎所有关于大麻/大麻素和认知的研究都在Young中进行 成人，很大程度上表明，急性给药会损害助记符和执行功能 内侧颞叶和前额叶皮层（这也是最容易下降的衰老和年龄较小的那些 相关的神经退行性疾病）。相反，一些研究表明大麻素可以发挥不同的作用 与年轻大脑相比，对老年人的影响，我们实验室的初步数据表明大麻可以 实际上在老年大鼠中选择性增强认知。确实，已经提出了大麻素作为潜力 与年龄相关的神经退行性疾病阿尔茨海默氏病（AD）和一些临床前的治疗 研究表明，大麻素可以减弱与AD病理学相关的标记（例如，神经炎症）。 然而，迄今为止评估大麻的老化研究非常有限，尚未使用任何大麻 本身或管理人员最常使用的管理途径（吸烟和口服 消耗）。因此，目前尚不清楚大麻实际上如何影响认知能力下降和 突触功能障碍和类似AD的病理学，导致老年受试者的认知障碍。 我们计划的长期目标是确定大麻如何影响衰老和AD的认知能力下降， 并确定这种效果的机制。当前建议的目的是建模两者 在良好的大鼠模型中，最常见的人类大麻使用（吸烟和口服消耗）的路线 与年龄有关的认知下降，并使用这些模型开始阐明大麻对行为的影响 与衰老和AD相关的神经生物学功能障碍。我们的总体假设是大麻 可以通过减弱与年龄相关的突触功能障碍，神经炎症和TAU来受益于衰老的认知 病理。 AIM 1将决定急性大麻如何影响年轻大鼠和老年大鼠的表现 作为支持大麻对老年受试者认知作用的突触机制。 AIM 2将评估 慢性大麻对年轻大鼠的认知以及兴奋性/抑制信号的影响 以及与年龄相关的认知障碍有关的炎症标记。 AIM 3将评估慢性的影响 使用新颖的老年大鼠基于AAV的方法，对广告状的Tau病理和认知大麻。这 提出的实验将是重要的，因为它们将提供有关是否以及是否和 与人类消费相关的大麻管理如何产生与年龄相关的认知下降的好处 和神经病理学。