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

项目概要： 老年人是美国增长最快的大麻使用者群体。老年人使用大麻的各种 原因包括疼痛、失眠、焦虑和娱乐。然而，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是在年轻人中进行的。 成人，并在很大程度上表明，急性管理损害记忆和执行功能介导的 内侧颞叶和前额叶皮层（也是最容易衰老和衰老的部位， 相关的神经退行性疾病）。相反，一些研究表明，大麻素可以发挥独特的作用， 与年轻人的大脑相比，大麻对老年人的影响，我们实验室的初步数据表明，大麻可以 实际上可以选择性地增强老年大鼠的认知能力。事实上，大麻素被认为是潜在的 治疗与年龄相关的神经退行性疾病阿尔茨海默病（AD），以及一些临床前 研究表明大麻素可以减弱与AD病理学相关的标志物（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，并且没有使用任何大麻 其本身或给药途径，模拟人们最常用的给药途径（吸烟和口服 消费）。因此，目前还不清楚大麻实际上是如何影响认知能力下降和 突触功能障碍和AD样病理，导致老年受试者的认知障碍。 我们项目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， 并确定这种影响的机制。本提案的目标是建立这两个模型， 在充分表征的大鼠模型中，人类使用大麻的最常见途径（吸烟和口服） 年龄相关的认知能力下降，并使用这些模型开始阐明大麻对行为的影响。 以及与衰老和AD相关的神经生物学功能障碍。我们的首要假设是大麻 通过减弱与年龄相关的突触功能障碍、神经炎症和tau蛋白， 病理目标1将确定急性大麻如何影响年轻成年和老年大鼠的表现，以及 作为支持大麻对老年受试者认知影响的突触机制。目标2将评估 慢性大麻对年轻成年和老年大鼠认知功能以及兴奋/抑制信号传导的影响 以及与年龄相关的认知障碍有关的炎症标志物。目标3将评估慢性 大麻对AD样tau病理学和认知的影响，使用一种新的，有针对性的基于AAV的方法在老年大鼠中进行。的 拟议的实验将是重要的，因为它们将提供有关是否和 与人类消费相关的大麻管理如何对与年龄相关的认知下降产生益处 和神经病理学

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.