Somatostatin Agonist Treatment for Cognitive Aging and Dementia

描述（由申请人提供）：阿尔茨海默病（AD）与特定的病理学特征相关，最突出的是淀粉样蛋白b肽（Ab）的细胞外沉积。Ab在脑中的积累导致斑块的形成，导致下游神经元死亡和痴呆。治疗AD的一个有希望的途径是通过使用选择性生长抑素受体（SSTR）激动剂。生长抑素已显示在患有AD的人类中减少，并且特异性地调节神经元脑啡肽酶活性，一种有效的Ab降解酶。此外，生长抑素受体亚型-4（SSTR 4）在新皮质和海马中高度表达，这些区域在AD患者中受到Ab积聚的显著影响。我们假设SSTR 4激动剂将增加脑啡肽酶活性，导致Ab浓度降低，从而增强学习和记忆。这项资助的目的是评估我们的新型SSTR 4激动剂减轻在SAMP 8和转基因APPswe小鼠中观察到的记忆和学习下降的能力，以及脑啡肽酶和Ab的相应改变。这次考试有三个目的。（1.）评估我们的新化合物在大脑中的脑摄取和区域分布。这将使我们能够评估各种化合物充分进入大脑的潜在可行性，确定它们到达大脑的哪些区域，以及为后续目标建立适当的剂量范围。（2.）基于aim-1，将评价所选SSTR 4激动剂在小鼠模型中的学习和记忆行为，所述小鼠模型显示与增加的Ab积累相关的学习和记忆缺陷。这将使我们能够确定治疗相关的学习和记忆保持变化。（3.）行为评价后，将对提取的脑组织进行分子分析，以确定激动剂处理对Ab、SSTR 4、淀粉样前体蛋白（APP）和脑啡肽酶（NEP）变化的影响。这些目标将使我们能够直接比较行为结果与AD病理学的分子标识符，关于我们的SSTR 4激动剂的治疗。总之，这些分析将为使用SSTR 4激动剂治疗AD提供新的信息，并进一步阐明A2假说。这项研究涉及国家土著发展战略和国家执行局的优先事项。公共卫生相关性：阿尔茨海默病（AD）与淀粉样蛋白-b肽（Ab）水平升高相关，其作为病理触发剂最终导致神经元死亡和痴呆。治疗AD的一个有希望的途径是使用选择性和稳定的生长抑素受体（SSTR）激动剂，其可以通过增强酶降解过程来减少Ab。本研究将使用已建立的模型和AD病理学评估来评估我们的新型SSTR激动剂减轻脑中Ab浓度以及学习和记忆保持的能力。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is associated with specific pathological features, the most prominent being extracellular deposits of amyloid b-peptide (Ab). The accumulation of Ab in the brain results in the formation of plaques, leading to down-stream neuronal death and dementia. A promising avenue for treatment of AD is through the use of selective somatostatin receptor (SSTR) agonists. Somatostatin has been shown to be decreased in humans suffering from AD and specifically regulates neuronal neprilysin activity, a potent Ab-degrading enzyme. Additionally, the somatostatin receptor subtype-4 (SSTR4) is highly expressed in neocortex and hippocampus, areas significantly affected by Ab accumulation in AD patients. We hypothesize that SSTR4 agonists will increase neprilysin activity in the brain leading to decreased Ab concentrations, enhancing learning and memory. The objectives of this grant are to evaluate our novel SSTR4 agonists in their ability to mitigate the decline in memory and learning observed in SAMP8 and transgenic APPswe mice, as well as the corresponding alterations in neprilysin and Ab. This examination has three aims. (1.) Evaluate brain uptake and regional distribution of our novel compounds within the brain. This will allow us to assess the potential viability of respective compounds to adequately enter the brain, establish which regions of the brain they get to, as well as establish appropriate dosing ranges for subsequent aims. (2.) Based on aim-1, selected SSTR4 agonists will be evaluated for learning and memory behavior in mouse models which display learning and memory deficits associated with increased Ab accumulation. This will allow us to identify treatment associated changes in learning and memory retention. (3.) After behavioral evaluations, molecular analyses will be performed on extracted brain tissues to determine the effect of agonist treatment on changes in Ab, SSTR4, amyloid precursor protein (APP) and neprilysin (NEP). These aims will allow us to directly compare the behavioral outcomes with molecular identifiers of AD pathology, with regards to treatment with our SSTR4 agonists. Taken together these analyses will provide new information into the use of SSTR4 agonists for the treatment of AD, as well as shed additional light on the A2 hypothesis. This study addresses priorities of both the NINDS and NIA. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is associated with elevated levels of Amyloid-b peptide (Ab), which acts as a pathological trigger culminating in neuronal death and dementia. A promising avenue for treating AD is in the use of selective and stable somatostatin receptor (SSTR) agonists, which may act to reduce Ab through enhancement of enzymatic degradative processes. This research will evaluate our novel SSTR agonists as to their ability to mitigate Ab concentrations in the brain in conjunction with learning and memory retention, using established models and assessments of AD pathology.