Linking Olfactory deficits to Neurodegenerative Disorders

将嗅觉缺陷与神经退行性疾病联系起来

• 批准号: 9164889
• 负责人: SUKUMAR VIJAYARAGHAVAN
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9164889
• 关键词: 3-Dimensional; Affect; Alzheimer' s Disease; Amygdaloid structure; Animals; Anosmia; Area; Biological Markers; Brain; Breeding; Cell Death; Cells; Chimeric Proteins; Clinical; Cognitive deficits; Corpus striatum structure; Coupled; Dementia; Discrimination; Disease; Drug Design; Early Intervention; Early treatment; Environment; Functional disorder; Genes; Genetic Predisposition to Disease; Grant; Hippocampus (Brain); Image; Impaired cognition; Lewy Bodies; Light; Link; Memory; Microscopy; Modality; Moods; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Odors; Olfactory Receptor Neurons; Output; Parkinson Disease; Pathology; Predisposition; Process; Research; Route; Sensory; Smell Perception; Staging; Symptoms; Synapses; System; Techniques; Testing; Thalamic structure; Time; Tissues; Tomatoes; Travel; Work; alpha synuclein; basal forebrain; basal forebrain cholinergic neurons; base; beta amyloid pathology; cholinergic; cholinergic neuron; design; dopaminergic neuron; entorhinal cortex; mitral cell; mouse model; mutant; nerve supply; neurotoxicity; olfactory bulb; overexpression; piriform cortex; pre-clinical; premature; synuclein; tau Proteins; therapy design

Project Summary Loss of cholinergic innervation is an early pathological sign in many neurodegenerative disease like Alzheimer's disease (AD) and Parkinson's disease (PD) and it is thought to underlie cognitive deficits in these diseases. Another early symptom, one that precedes the canonical symptoms of these diseases by many years is deficits in olfaction. It stands to reason that if we can provide a mechanistic explanation linking these early deficits to AD and PD, we will have an early biomarker for these diseases and allow for the design of strategies for early intervention and treatment. In this proposal we test the idea that olfactory insults can cause the degeneration of central neurons that express genes that confer susceptibility to degeneration. To test this idea, we will use mouse models that over-express these genes only in cholinergic neurons. The two genes being tested are the tau, implicated in AD (and now in PD) and the A53T mutant α synuclein (A53T αsyn) along with a flurophore (GFP or Td-Tomato). The mice will be subject to either chemically-induced anosmia or treatments that specifically target dopaminergic neurons in the olfactory bulb (intranasal MPTP or stereotactically injected 6-OHDA). We will then examine the cholinergic projections in these mice. For this we will use the CLARITY technique for rendering the brain transparent coupled with light sheet microscopy that allows us to image deep into tissues. Using this technique we will reconstruct and render in 3-D the cholinergic innervation from the basal forebrain to the olfactory bulb. This will allow us to compare changes in cholinergic innervation under conditions of olfactory insults. This project is the first attempt at providing a link between olfactory dysfunction and the cognitive symptoms seen in AD and PD. It will also be the first to provide a detailed 3-D rendering of the basal forebrain cholinergic system. Results from this study will provide the basis for using olfactory dysfunction as an early biomarker for neurodegenerative diseases.

项目概要 胆碱能神经支配的丧失是许多神经退行性疾病的早期病理征兆，例如 阿尔茨海默病（AD）和帕金森病（PD）被认为是认知缺陷的根源 这些疾病。另一种早期症状，先于这些疾病的典型症状 多年来嗅觉缺陷。按理说，如果我们能提供一个机制上的解释 将这些早期缺陷与 AD 和 PD 联系起来，我们将拥有这些疾病的早期生物标志物，并允许 早期干预和治疗策略的设计。 在这个提案中，我们测试了嗅觉损伤会导致中枢神经元退化的想法 表达赋予退化易感性的基因。为了测试这个想法，我们将使用鼠标模型 仅在胆碱能神经元中过度表达这些基因。被测试的两个基因是 tau 基因， 与 AD（现在在 PD）和 A53T 突变体 α 突触核蛋白 (A53T αsyn) 以及荧光团有关 （GFP 或 Td-番茄）。 这些小鼠将接受化学诱导的嗅觉丧失或专门针对小鼠的治疗。 嗅球中的多巴胺能神经元（鼻内 MPTP 或立体定向注射 6-OHDA）。 然后我们将检查这些小鼠的胆碱能投射。为此，我们将使用 CLARITY 使大脑透明的技术与光片显微镜相结合，使我们能够成像 深入组织。使用这种技术，我们将重建并以 3D 形式渲染胆碱能神经支配 基底前脑到嗅球。这将使我们能够比较胆碱能神经支配的变化 在嗅觉侮辱的情况下。 该项目是首次尝试提供嗅觉功能障碍和认知功能之间的联系 AD 和 PD 中出现的症状。它还将是第一个提供基础的详细 3D 渲染的产品。 前脑胆碱能系统。这项研究的结果将为利用嗅觉功能障碍作为治疗提供依据 神经退行性疾病的早期生物标志物。