New Strategy to Fight Selective Cholinergic Neuronal Loss in Alzheimer Disease

对抗阿尔茨海默病选择性胆碱能神经元损失的新策略

• 批准号: 8598020
• 负责人: WILLIAM Z. SUO
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598020
• 关键词: Acetylcholine; Acute; Address; Affect; Age; Age-Months; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein Precursor; Animal Model; Animals; Apoptosis; Apoptotic; Asses; Autopsy; Autoreceptors; Behavior; Biogenesis; Brain; Cell Culture Techniques; Cell Death; Cells; Cognitive; Cognitive deficits; Crossbreeding; Cyclic AMP; Data; Defense Mechanisms; Dementia; Disease; Disease Progression; Dose; Energy Metabolism; Exhibits; GRK5 gene; General Population; Gliosis; Goals; Health; Hippocampus (Brain); Histology; Human; Hyperactive behavior; Impaired cognition; Inflammation Mediators; Injury; Intercellular Fluid; Knockout Mice; Link; Measures; Mediating; Mitochondria; Modeling; Mus; Muscarinic M1 Receptor; Muscarinic M2 Receptor; Muscarinics; Mutation; Nerve Degeneration; Neurites; Neurons; Outcome; Oxidative Stress; Pathologic; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Prevention; Process; Prosencephalon; Research Support; Rewards; Role; Sampling; Severities; Signal Pathway; Staging; Supportive care; Tg2576; Therapeutic Studies; Time; Transgenic Mice; Translating; Veterans; anthranilamide; axonopathy; basal forebrain; basal forebrain cholinergic neurons; brain cell; cholinergic; cholinergic neuron; comparative efficacy; desensitization; drug testing; fighting; functional loss; human GRK5 protein; improved; in vivo; innovation; killings; mild cognitive impairment; mouse model; mutant; neurodegenerative dementia; neuron loss; novel; overexpression; postsynaptic; presynaptic; prevent; therapeutic target

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative dementia characterized by selective cholinergic neurodegeneration. Millions of Americans are affected, but there are no disease-modifying treatments. This is, in part, because we do not know why the cholinergic neurons are more vulnerable than others, and therefore do not have specific strategy to protect them. In fact, there is even not an animal model that recaptures the selective and robust basal forebrain cholinergic (BFC) neuronal cell loss that is typical of AD. The absence of a model severely limits relevant mechanistic and therapeutic studies. We have now developed a transgenic mouse that exhibits the most essential features of cholinergic neurodegenerative process of human AD, including the robust BFC neuronal loss. These mice have G protein- coupled receptor kinase-5 (GRK5) deficiency (as severe as in human AD) and overexpress Swedish mutant of ¿-amyloid precursor protein. The heterozygous double defective mice (hereafter abbreviated as GAP mice) selectively lost one-third of their BFC neurons at 18 months of age. We therefore propose that GRK5 deficiency is an "Alzheimer-selective" factor that makes cholinergic neurons more vulnerable to degeneration. GRK5 deficiency was previously linked to AD because it could be caused by ¿-amyloid (A¿) and oxidative stress. There is a severe GRK5 deficiency in human AD brains. We now have preliminary findings that document that GRK5 deficiency increases cholinergic vulnerability both in cell cultures and in intact mice. GRK5 deficiency leads to reduced hippocampal acetylcholine release, cholinergic axonopathy (without cell death), and mild cognitive impairment. GRK5 deficiency also exaggerates Ass accumulation and gliosis. Mechanistically, all phenotypes of GRK5 deficiency appear to be attributable to an impaired desensitization of M2 muscarinic acetylcholine autoreceptor (M2). Extant research supports the concept that impaired M2 desensitization leads to persistent inhibition of the cAMP-dependent signaling pathway and that this inhibition reduces intrinsic defense mechanisms of cholinergic cells and leads to their vulnerability. We hypothesize that GRK5 deficiency selectively causes cholinergic vulnerability via impaired M2 desensitization; and that blocking presynaptic M2 receptors would prevent cholinergic neurodegeneration. We propose 4 Specific Aims to consolidate our preliminary findings and address our hypothesis. Specific Aim 1). Characterize the time course of cholinergic neurodegeneration and cognitive decline in GAP mice; Specific Aims 2 and 3). Compare the efficacies of M2 blockade and M1 stimulation in improving cognitive deficits and preventing cholinergic neurodegeneration in GAP mice; and Specific Aim 4). Translate the major findings from GAP mice to human AD by examining all these changes in human AD brain samples and correlating them with severity of dementia. We hope by the end of the project, we will have characterized an innovative animal model (GAP mice) of human AD for its detailed time course of cholinergic neurodegeneration and cognitive decline. We will have validated the innovative concept that GRK5 deficiency causes selective cholinergic vulnerability and that vulnerability can be prevented by M2 blockade but not M1 stimulation. In addition, at a principle level, we will have also proven the efficacy of a novel drug, AAD23, in preventing BFC neurodegeneration. We hope to find that the degree of GRK5 deficiency in human AD samples correlates with the severity of cholinergic neurodegeneration. This finding will provide rationale for trials of M2 receptor blockers for the prevention of cholinergic neurodegeneration in human AD.

描述（由申请人提供）： 阿尔茨海默病（AD）是一种以选择性胆碱能神经变性为特征的神经退行性痴呆。数百万美国人受到影响，但没有缓解疾病的治疗方法。部分原因是我们不知道为什么胆碱能神经元比其他神经元更脆弱，因此没有具体的策略来保护它们。事实上，甚至没有一种动物模型能够重现 AD 典型的选择性和稳健的基底前脑胆碱能 (BFC) 神经元细胞损失。模型的缺乏严重限制了相关的机制和治疗研究。 我们现在已经开发出一种转基因小鼠，它表现出人类 AD 胆碱能神经退行性过程的最基本特征，包括强大的 BFC 神经元损失。这些小鼠患有 G 蛋白偶联受体激酶 5 (GRK5) 缺陷（与人类 AD 一样严重），并且过度表达 β-淀粉样蛋白前体蛋白的瑞典突变体。杂合双缺陷小鼠（以下简称GAP小鼠）在18月龄时选择性丧失了三分之一的BFC神经元。因此，我们认为 GRK5 缺乏是一种“阿尔茨海默氏症选择性”因素，使胆碱能神经元更容易退化。 GRK5 缺乏以前被认为与 AD 有关，因为它可能是由 β-淀粉样蛋白 (A¿) 和氧化应激引起的。人类 AD 大脑中存在严重的 GRK5 缺陷。我们现在的初步发现表明，GRK5 缺乏会增加细胞培养物和完整小鼠的胆碱能脆弱性。 GRK5 缺乏会导致海马乙酰胆碱释放减少、胆碱能轴突病（无细胞死亡）和轻度认知障碍。 GRK5 缺乏还会加剧 Ass 积累和神经胶质增生。从机制上讲，GRK5 缺陷的所有表型似乎均可归因于 M2 毒蕈碱乙酰胆碱自身受体 (M2) 脱敏受损。现有研究支持这样的观点，即 M2 脱敏受损会导致 cAMP 依赖性信号通路的持续抑制，并且这种抑制会降低胆碱能细胞的内在防御机制并导致其脆弱性。 我们假设 GRK5 缺陷通过 M2 脱敏受损选择性地导致胆碱能脆弱性；阻断突触前 M2 受体可以预防胆碱能神经变性。我们提出 4 个具体目标来巩固我们的初步发现并解决我们的假设。具体目标 1).描述 GAP 小鼠胆碱能神经变性和认知能力下降的时间过程；具体目标 2 和 3)。比较 M2 阻断和 M1 刺激在改善 GAP 小鼠认知缺陷和预防胆碱能神经变性方面的功效；和具体目标 4)。通过检查人类 AD 大脑样本中的所有这些变化并将其与痴呆症的严重程度相关联，将 GAP 小鼠的主要发现转化为人类 AD。 我们希望在项目结束时，我们能够确定人类 AD 的创新动物模型（GAP 小鼠）的特征，了解其胆碱能神经变性和认知能力下降的详细时间过程。我们将验证这一创新概念，即 GRK5 缺乏会导致选择性胆碱能脆弱性，并且这种脆弱性可以通过 M2 阻断而非 M1 刺激来预防。此外，在原则层面上，我们还将证明一种新药AAD23在预防BFC神经变性方面的功效。我们希望发现人类 AD 样本中 GRK5 缺乏的程度与胆碱能神经变性的严重程度相关。这一发现将为 M2 受体阻滞剂预防人类 AD 胆碱能神经变性的试验提供依据。