POTENTIAL ROLE OF EPILEPSY IN ALZHEIMER? DISEASE

癫痫在阿尔茨海默病中的潜在作用？

基本信息

批准号：
7624806
负责人：
Lennart Mucke
金额：
$ 19.1万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7624806
关键词：
10p Abbreviations Acetylcholine Acute Adverse effects Affect Aftercare Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Precursor Analysis of Variance Antiepileptic Agents Anxiety Apolipoprotein E Autopsy Behavioral Biochemical Brain Brain region Butyric Acids Calcium Calcium Channel Cholinergic Receptors Clinical Trials Cognitive deficits Communication impairment Complement Corpus striatum structure Data Dementia Development Disease Disorientation Dose Drug Combinations Drug Delivery Systems Electroencephalogram Electroencephalography Enkephalins Enrollment Environment Epilepsy Frequencies Frontotemporal Dementia Frontotemporal Lobar Degenerations Funding GABA Receptor Genetic Predisposition to Disease Genetically Engineered Mouse Glutamate Receptor Goals Heterogeneity Hippocampus (Brain)Hour Human Immunohistochemistry Impaired cognition Incidence Individual Institutes Isoxazoles Learning Lewy Body Disease Light Link Measures Mediating Mediator of activation protein Memory Memory impairment Messenger RNA Methionine Enkephalin Modeling Molecular Motor Seizures Mus N-Methyl-D-Aspartate Receptors Neurofibrillary Tangles Neurologic Neurons Nicotinic Receptors Outcome Measure Pathogenesis Patients Peptides Pharmaceutical Preparations Phosphoric Monoester Hydrolases Platelet-Derived Growth Factor Play Polyacrylamide Gel Electrophoresis Prevention Process Propionic Acids Proteins Public Health Research Resistance Reverse Transcriptase Polymerase Chain Reaction Role Safety Seizures Severities Sodium Channel Sodium Dodecyl Sulfate-PAGE Stroke Telemetry Testing Tissues Transgenic Mice Transgenic Organisms Western Blotting apolipoprotein E-4 behavior test calbindin cooperative study dentate gyrus disorder control drug efficacy entorhinal cortex familial Alzheimer disease genetic manipulation genetic risk factor granule cell insight mild neurocognitive impairment morris water maze mouse model neuropathology neuropeptide Y neuropeptide Y-Y1 receptor novel strategies pre-clinical preproenkephalin prevent receptor research study response voltage

项目摘要

Within the overarching theme of "New Approaches to Heterogeneity in Dementia," Project 2 has focused on Alzheimer's disease (AD). The insights we gained during the preceding funding period and the ever increasing threat AD poses to public health have motivated us to maintain this focus in the current proposal. We will also continue to utilize genetically engineered mice with neuronal expression of human amyloid precursor proteins (hAPP) and amyloid-p (AP) peptides, because there is substantial evidence for mechanistically informative overlap between these models and the human condition. In our original application, we promised to shed light on the processes by which Ap elicits neuronal deficits. We found that neurons in the dentate gyrus and entorhinal cortex - brain regions affected early and severely by AD - are particularly vulnerable to the Ap-induced depletion of proteins that are critical for learning and memory. Several molecules were identified that may mediate this process. We also identified strategies to prevent Apinduced neuronal deficits in hAPP mice. Our new proposal builds on the most promising findings we obtained during the preceding funding period. Specifically, we discovered that the depletion of calciumdependent proteins and associated memory deficits in hAPP mice are likely caused by spontaneous nonconvulsive epileptiform activity in cortical and hippocampal networks. Memory deficits, depletions of calciumdependent proteins, and abnormal network activity could be prevented in hAPP mice through a genetic manipulation that blocks neuronal overexcitation. Independent lines of evidence suggest that epileptiform activity may also play a pathogenic role in humans with AD. We therefore postulate that aberrant excitatory neuronal activity might play an important causal role in the pathogenesis of Ap-induced cognitive impairments in hAPP mice and in AD. This hypothesis will be tested in three new specific aims. In Aim 1, we will examine whether markers of abnormal neuronal activity are increased in brains of" patients with mild cognitive impairment (MCI), AD, or other dementias. In Aim 2, we will test whether available anti-epileptic drugs can prevent or reverse EEC abnormalities in AD-related mouse models. In Aim 3, we will test whether any of these anti-epileptic drugs can also prevent or reverse cognitive deficits in these models. Confirmation of these untested hypotheses should help elucidate the mechanisms that underlie Ap-dependent cognitive deficits and pave the way for the development of better treatments for AD. Although there is plenty of ' evidence for a potential role of epilepsy in the development of AD, there appear to have been no rigorous clinical trials of anti-epileptic drugs in patients with MCI or early AD. The experiments described in our application could pave the path towards such a clinical trial and provide critical guidance in the selection of the most promising drugs. The proposed ADRC will provide an ideal environment for us to achieve these goals.

在“痴呆症异质性新方法”的总体主题中，项目 2 重点关注关于阿尔茨海默病（AD）。我们在之前的融资期间和以后的融资期间获得的见解 AD 对公共健康造成的日益严重的威胁促使我们在当前提案中保持这一重点。我们还将继续利用神经元表达人类淀粉样蛋白的基因工程小鼠前体蛋白 (hAPP) 和淀粉样蛋白 (AP) 肽，因为有大量证据表明这些模型与人类状况之间在机制上信息重叠。在我们原来的在应用程序中，我们承诺阐明 Ap 引发神经元缺陷的过程。我们发现齿状回和内嗅皮层中的神经元（受 AD 影响较早且严重的大脑区域）特别容易受到 Ap 引起的对学习和记忆至关重要的蛋白质的消耗。已鉴定出几种可能介导这一过程的分子。我们还确定了预防Apinduced的策略 hAPP 小鼠的神经元缺陷。我们的新提案建立在我们最有希望的发现之上在之前的资助期内获得的。具体来说，我们发现钙依赖性的消耗 hAPP 小鼠中的蛋白质和相关记忆缺陷可能是由自发性非惊厥引起的皮质和海马网络中的癫痫样活动。记忆力减退、钙依赖性消耗 hAPP 小鼠中的蛋白质和异常网络活动可以通过遗传来预防阻止神经元过度兴奋的操作。独立的证据表明癫痫样活性也可能在患有 AD 的人类中发挥致病作用。因此，我们假设异常兴奋神经元活动可能在 Ap 诱导的认知障碍的发病机制中发挥重要的因果作用 hAPP 小鼠和 AD 中的损伤。这一假设将在三个新的具体目标中得到检验。在目标 1 中，我们将检查“轻度”患者大脑中异常神经元活动的标记是否增加认知障碍 (MCI)、AD 或其他痴呆症。在目标2中，我们将测试是否有可用的抗癫痫药物药物可以预防或逆转 AD 相关小鼠模型中的 EEC 异常。在目标 3 中，我们将测试是否这些抗癫痫药物中的任何一种也可以预防或逆转这些模型中的认知缺陷。确认这些未经检验的假设应该有助于阐明 Ap 依赖性认知的机制缺陷并为开发更好的 AD 治疗方法铺平道路。虽然有很多‘ 尽管目前尚无严格的证据表明癫痫在 AD 的发展中具有潜在作用。抗癫痫药物治疗 MCI 或早期 AD 患者的临床试验。我们描述的实验应用程序可以为此类临床试验铺平道路，并为选择药物提供关键指导最有前途的药物。拟议的 ADRC 将为我们实现这些目标提供理想的环境目标。