Prelimbic somatostatin peptide signaling in binge ethanol consumption

暴饮暴食中的边缘前生长抑素肽信号传导

• 批准号: 10721995
• 负责人: Nicole Ashley Crowley
• 金额: $ 30.47万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-20 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721995
• 关键词: Administrative Supplement; Adult; Aging; Agitation; Agonist; Alcohol consumption; Alcohols; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Award; Behavior; Behavioral; Biological; Brain; COVID-19 pandemic; Catabolism; Cognition; Cognitive; Complement; Data; Development; Diagnosis; Disease; Enzymes; FDA approved; Funding; Future; Goals; Human; Impaired cognition; Individual; Literature; Mediator; Memory; Neprilysin; Nerve Degeneration; Neurobiology; Neurons; Neuropeptides; Octreotide; Outcome; Parents; Pathologic; Pathway interactions; Peptide Signal Sequences; Peptides; Population; Positioning Attribute; Public Health; Risk; Risk Factors; Senile Plaques; Somatostatin; Somatostatin Receptor; Testing; Work; abeta deposition; alcohol use disorder; behavior change; binge drinking; dementia risk; drinking behavior; executive function; experimental study; glial activation; healthy aging; improved; innovation; insight; neuroprotection; neuropsychiatry; optogenetics; prevent; reduced alcohol use; resilience; success; therapeutic target; transmission process

ABSTRACT Alcohol use is a major risk factor for Alzheimer’s Disease and Related Dementias (ADRD), but the biological mechanisms by which alcohol consumption leads to this increased risk are poorly understood. The aims of the parent award are to understand binge drinking-induced reductions in somatostatin peptide signaling within the prelimbic cortex – a key nexus for executive functioning, memory, and other cognitive-related behavior. In this supplement, we will extend this work to understand whether this alcohol-induced reduction in somatostatin is a mechanism of increase amyloid beta plaques. We will build upon existing literature suggesting that somatostatin is a key regulator of the enzyme neprilysin, known to prevent the initial formation of plaques, and that binge drinking breaks down this preventative pathway. We will explore 1) how binge drinking leads to reductions in SST peptide expression and transmission, and how this relates to reductions in neprilysin and amyloid beta buildup; 2) the ability for somatostatin agonists to reduce both cognitive decline and alcohol-induced cognitive decline, including in memory and exploration-related tasks. By complementing experiments in the parent award, we will collect new data on this innovative hypothesis for alcohol-induced ADRD risk. Public Health Statement: This administrative supplement will expand our understanding of the basic mechanisms by which binge alcohol drinking contributes to the cognitive decline seen in Alzheimer’s Disease and Related Dementias. A better mechanistic understanding of this mediator of decline is necessary for targeting both treatments and preventative efforts.

摘要 饮酒是阿尔茨海默病和相关痴呆(ADRD)的主要危险因素，但生物学上的 饮酒导致这种风险增加的机制尚不清楚。该计划的目标是 家长奖是了解酗酒导致体内生长抑素多肽信号的减少 大脑皮层--执行功能、记忆和其他认知相关行为的关键纽带。在这 补充，我们将扩展这项工作，以了解酒精诱导的生长抑素减少是否是一种 淀粉样β蛋白斑块增多的机制。我们将在现有文献的基础上提出生长抑素 是neprilysin酶的关键调节因子，已知它可以防止斑块的初始形成，而这种狂欢 饮酒破坏了这种预防途径。我们将探索酗酒是如何导致减少 SST多肽的表达和传递，以及这与Neprilysin和淀粉样β蛋白减少的关系 2)生长抑素激动剂减少认知功能衰退和酒精诱导的认知功能的能力 下降，包括记忆和与探索相关的任务。通过补充家长奖中的实验， 我们将收集关于酒精引起的ADRD风险的这一创新假说的新数据。公共卫生 声明：本行政副刊将扩大我们对以下基本机制的理解 酗酒会导致阿尔茨海默病和相关痴呆症患者的认知能力下降。 更好地从机制上理解这种递减的介体对于针对治疗和 预防性的努力。