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）是一种神经变性，但没有疾病改良的治疗方法。甲骨素胆碱能（BFC）神经元细胞的损失是典型的AD，我们现在已经开发了相关的机械和治疗性研究。神经元损失。 - 淀粉样蛋白的蛋白质。经过 - 淀粉样蛋白（a¿）和氧化应激，GRK5缺乏症的所有表型似乎是对M2毒蕈碱乙酰氨基盐c的脱敏脱敏（M2）。胆碱能通过M2脱敏，我们提出了4个特定的目的，以巩固我们的初步发现A a A。 M2阻滞和M1刺激在改善缺陷和防止GAP小鼠特定目标中的神经退行性方面的效率4）。我们的终结是胆碱能神经变性和认知能力下降的动物模型（GAP小鼠）的表征。我们希望对BFC神经退行性的疗效，我们希望能够找到GRK5的疗效。