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

基本信息

批准号：
8246191
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
项目类别：
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/8246191
关键词：
Acetylcholine Acute Address Affect Age Age-Months Agonist Alzheimer&apos s Disease Alzheimer&apos 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 neurocognitive impairment mouse model mutant neurodegenerative dementia neuron loss novel overexpression postsynaptic presynaptic prevent therapeutic target

项目摘要

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）：阿尔茨海默氏病（AD）是一种具有选择性胆碱能神经变性的神经退行性痴呆。数以百万计的美国人受到影响，但没有改善疾病的治疗方法。这部分是因为我们不知道为什么胆碱能神经元比其他人更脆弱，因此没有保护它们的特定策略。实际上，甚至没有一个动物模型可以重新接收典型的AD的选择性且坚固的基本前脑胆碱能（BFC）神经元细胞损失。缺乏模型严重限制了相关的机械和治疗研究。现在，我们已经开发了一种转基因小鼠，该小鼠表现出人类AD的胆碱能神经退行性过程的最重要特征，包括强大的BFC神经元损失。这些小鼠具有G蛋白偶联受体激酶-5（GRK5）缺乏症（与人AD一样严重）和过表达的瑞典突变体的 - 淀粉样蛋白前体蛋白。在18个月大时，杂合的双缺陷小鼠（以后缩写为间隙小鼠）有选择地损失了其BFC神经元的三分之一。因此，我们建议GRK5缺乏症是一种“阿尔茨海默氏症选择性”因素，它使胆碱能神经元更容易受到变性。 GRK5缺乏以前与AD相关，因为它可能是由 - 淀粉样蛋白（a。）和氧化应激引起的。人类广告大脑中的GRK5缺乏严重。现在，我们有初步的发现表明，GRK5缺乏症会增加细胞培养物和完整小鼠中的胆碱能脆弱性。 GRK5缺乏会导致海马乙酰胆碱释放，胆碱能轴突病（无细胞死亡）和轻度认知障碍。 GRK5缺乏症也夸大了屁股的积累和神经胶质病。从机械上讲，GRK5缺乏症的所有表型似乎都归因于M2毒蕈碱乙酰胆碱自身受体受体（M2）的脱敏受损。现有的研究支持了损害M2脱敏的概念会导致对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缺乏症通过M2脱敏而有选择地引起胆碱能脆弱性。并且阻断突触前的M2受体会预防胆碱能神经退行性。我们提出了4个具体目标，以巩固我们的初步发现并解决我们的假设。具体目的1）。表征间隙小鼠的胆碱能神经退行性变化和认知下降的时间过程；具体目标2和3）。比较M2阻滞和M1刺激在改善认知缺陷方面的效率和防止GAP小鼠中胆碱能神经变性的效率；和特定目标4）。通过检查人类AD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，从间隙小鼠转化为人类AD的主要发现。我们希望在项目结束时，我们将以人类广告的创新动物模型（GAP小鼠）为特征，因为它的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GRK5缺乏会引起选择性胆碱能脆弱性的创新概念，并且可以通过M2阻断而不是M1刺激来预防脆弱性。此外，在原始水平上，我们还将证明一种新型药物AAD23在防止BFC神经变性中的效率。我们希望发现人类AD样品中GRK5缺乏程度与胆碱能神经退行性的严重程度相关。这一发现将为M2受体阻滞剂试验提供预防人类AD中胆碱能神经退行性的基本原理。